HIV-1 strategies to overcome the immune system by evading and invading innate immune system

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HIVAR-131; No. of Pages 12 HIV & AIDS Review xxx (2015) xxx–xxx

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Review Article

HIV-1 strategies to overcome the immune system by evading and invading innate immune system Mohammad A.Y. Alqudah a,*, Mahmoud M.M. Yaseen b, Mohammad M.S. Yaseen c a

Clinical Pharmacy, College of Pharmacy, Jordan University of Science and Technology, Irbid 22110, Jordan Medical Laboratory Sciences, College of Applied Medical Sciences, Jordan University of Science and Technology, Irbid 22110, Jordan c Public Health, College of Nursing, University of Benghazi, Benghazi, Libya b

A R T I C L E I N F O

A B S T R A C T

Article history: Received 26 July 2014 Received in revised form 8 July 2015 Accepted 16 July 2015 Available online xxx

HIV-1 infection is a major public health problem and an important cause of death among adults. In light of innate immune system being the first, rapid and nonspecific response, this highlights the importance of exploiting the active arms of innate immunity to eradicate the invader and triggering a more specific immune response, the adaptive immune system. Each type of cells in the innate immune system has a unique distribution and function in the body and therefore differs in their ability to induce adaptive immune arms according to the stimuli. Any functional defect or alteration in the innate immune system can affect the adaptive arms of the immune system in terms of failure to overcome the battlefield with the invader. This review focuses on the relevant function of each member of the innate immune system and sheds the light on detailed mechanisms about how this smart virus invades and evades the immune system which opens new insights into the immunology and therapeutic targeting of HIV-1 infection. ß 2015 Polish AIDS Research Society. Published by Elsevier Sp. z o.o. All rights reserved.

Keywords: Complement NK cells DC Macrophages Basophils Bacterial Translocation

1. Introduction Human immunodeficiency virus (HIV)-1 is a unique invader of the immune system that eventually leads to acquired immunodeficiency syndrome (AIDS) [1] if not treated. HIV has affected over 71 million people around the world since its emergence according

Abbreviations: HIV, human immunodeficiency virus; AIDS, acquired immunodeficiency syndrome; IL, interleukin; IFN, interferon; TNF, tumor necrosis factor; TRAIL, TNF-related apoptosis inducing ligands; DC, dendritic cells; NK, natural killer; MAC, membrane-attack complex; FH, factor H; Gp, glycoprotein; CR, complement receptor; FDC, follicular dendritic cell; MHC, major histocompatibility complex; BM, bone marrow; KIR, killer-cell immunoglobulin-like receptor; SHIV, SimianHuman Immunodeficiency Virus; MICA, MHC class-I polypeptide-related sequence A; ULBP, UL16 binding protein; ADCC, antibody dependent cellular cytotoxicity; LTNP, long-term non-progressors; APC, antigen presenting cells; DC-SIGN, Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin; GALT, gut associated lymphoid tissues; mDC, myeloid dendritic cells; pDC, plasmacytoid dendritic cells; TLR, Toll-Like Receptor; MDDC, monocyte derived dendritic cells; Th, helper T cells; Treg, regulatory T cells; IDO, indolemine 2,3dioxygenase; ART, antiretroviral therapy; HAART, highly active antiretroviral therapy; CNS, central nervous system; Ig, immunoglobulin; Nef, negative factor; Tat, Trans activator. * Corresponding author. Tel.: +962 02 7201000; fax: +962 02 7095123. E-mail address: [email protected] (Mohammad A.Y. Alqudah).

to UNAIDS reports [2]. The vast majority of HIV-1 infections are due to the exposure of mucosal surfaces to the virus during sexual contact [3]. Unfortunately, there is no protective vaccine yet available and the disease is not curable by the available therapeutic strategies [4]. There seems to be some gaps in knowledge regarding how the virus can invade our bodies, overcome the immune system and escape/impair the immune responses, particularly the innate immunity. The innate immune system represents the primary sentinel of our bodies against invaders. Indeed, the innate immune system of its both arms, the humoral and cellular components, collaborate either to eliminate invaders or to activate a more specific branch of the immune system, namely the adaptive immune system [5–9]. The mediation of specific arm of the adaptive immune responses has been shown to be substantially dependent on the participant arm(s) of the innate immune system. Hence, the potential role of innate immune system to determine the subsequent adaptive immune responses underscores its important role in primary and secondary defense responses [5–9]. Thus, alteration or impairment of the innate immune system components will remarkably affect the immune responses in total. In the case of HIV-1 infection, there is strong evidence that the maintenance of sufficient and efficient innate responses play a

http://dx.doi.org/10.1016/j.hivar.2015.07.004 1730-1270/ß 2015 Polish AIDS Research Society. Published by Elsevier Sp. z o.o. All rights reserved.

Please cite this article in press as: M.A.Y. Alqudah, et al., HIV-1 strategies to overcome the immune system by evading and invading innate immune system, HIV & AIDS Review (2015), http://dx.doi.org/10.1016/j.hivar.2015.07.004

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principal role in disease controlling as seen in a small group (<1%) of patients who are naturally able to control HIV-1 disease progression [10–18]. Therefore, targeting innate immune system components could be a novel therapeutic in management of HIV-1 infection [11–13]. In this review, we addressed new advances in our understanding of HIV-1 invasion and evasion strategies of the innate immune system to further clarify how the virus can overcome the battlefield with the immune system in HIV-1 progressors. In our discussion, we considered the complement system, natural killer (NK) cells, dendritic cells (DCs), basophils/ mast cells, and monocytes/macrophages. In addition, we made future recommendations regarding exploiting some ignored members of innate immune system to be further studied and used in the management of this grim infectious disease. 2. Complement system 2.1. Complement system and HIV The complement system is a set of about 40 soluble and membrane-bound proteins that play a critical role in defense as part of innate immune system that mediate humoral adaptive immune response [5,19]. Activation of complement components is crucial to the development of inflammatory reactions as one of the earliest defense lines against invading pathogens including viruses [20]. The threshold for B cell activation in the presence of both complement and antigen is lowered due to the increased immunogenicity compared with a naive antigen [19]. This illustrates the important role of complement system as a humoral arm of the innate immune system that participates in priming and boosting the adaptive immune response. There are three pathways of complement activation: the classical, lectin and alternative pathways. The end product of complement activation of all three pathways is cell lysis as a result of membrane-attack complex (MAC) formation [21]. Although complement proteins lack the specificity to discriminate between self and non-self-targets, host cells express several membrane proteins (complement regulatory proteins) that inhibit complement activation and MAC formation at several stages of complement cascade, thus preventing self-damage [22–27]. These complement regulatory proteins include CD59, CD55, and CD46 [22–26], in addition to the fluid phase of complement regulatory protein factor H (FH) [27]. Worthy to note that complement activation or downregulation is tightly regulated process, once the complement activation exceeded the capacity of complement regulatory proteins to inhibit its action, then the activation process keeps continuing, and vice versa. 2.2. HIV-1 invasion and evasion of complement system After exposure to HIV-1 (most commonly via sexual transmission), the virus might succeed to cross the epithelial layer of the mucous membrane via different mechanisms [28]. These include but not limited to transcytosis, dendritic cells (DCs), and complement system contribution (Fig. 1) [29]. In fact, the complement system is activated against HIV-1 (even in the absence of antibodies) through direct interaction of viral envelope glycoproteins (Gp) Gp120 and Gp41 with complement proteins that might lead to viral inactivation [30–32]. It has been shown that complement system activation against HIV-1 is responsible to destruct and clear a portion of plasma HIV-1 in vivo [32]. The observed susceptibility of some of HIV-1 particles in plasma to complement-mediated lysis in this study may be due to the low complement regulatory proteins incorporation onto HIV-1 envelop or to the excess exposure to complement activating proteins, since HIV-1 particles with sufficient complement regulatory proteins on

their surfaces are resistant. These data suggest a potential role for complement activating proteins in activating complement system and provide evidence for the important role of the complement system in priming and boosting the innate and adaptive immune responses even in HIV-1 infection. In a recent study by Tjomsland et al. [33], it has been shown that complement-opsonization of HIV-1 particles could affect the antigen presentation process in DCs. In this study, both mature and immature DCs were significantly enhanced to present complement-opsonized HIV-1 particles via MHC class-I by 63% and 72% respectively, compared to non-opsonized HIV-1 particles, indicating that complement-opsonization routes more HIV-1 particles toward presentation via MHC class-I [33]. Conversely, another more recent study by Ellega˚rd et al. [34] has shown that complement-opsonization of HIV-1 particles decreases the antiviral responses in immature DCs, and this process is entirely dependent on the engagement of complement receptor 3 (CR3) that expressed on DCs with opsonized HIV-1 particles and abrogation of TLR-8 mediated responses. Several studies have demonstrated that HIV-1 has established several mechanisms to evade complement-mediated lysis at both free virus and infected cell level. As described earlier, human cells constitutively express variety of complement regulatory proteins. The virus incorporates different cellular membrane complement regulatory proteins on its envelope during budding process [35,36]. In addition, it incorporates FH via its glycoproteins (Gp120 and Gp41) thereby HIV-1 establishes a way to resist complement-mediated lysis [37]. Of note, the complement activation or downregulation on HIV-1 envelop heavily depends on the amount of recruited complement regulatory proteins. Interestingly, if the complement activation fail to mediate HIV-1 lysis, the virus can hijack the complement system and exploit it to enhance its infectivity toward cells that express CRs [38–40], including monocytes/macrophage, DCs [39,40], thymocytes [41], as well as other non-immune cells such as erythrocytes [38]. In turn, this may facilitate transinfection of CD+ T cells. For instance, complement-opsonization of HIV-1 results in 2- to 3-fold enhancement of trans-infection of CD4+ T cells via DCs [40]. In another instance, erythrocytes might facilitate wide dissemination of opsonized HIV-1 particles seeding in lymphoid organs where the HIV-1 can be trapped by target cells [42]. Moreover, trapping of HIV-1 and trans-infection of T cells by B cells [43] and follicular dendritic cells (FDCs) [44] using complement receptor 2 (CR2) have been reported. On their surface, FDC can trap opsonized-HIV particles with complement or complement-antibody complex without being infected for several months. These trapped virions have been shown to be highly infectious to CD4+ T cells and resistant to antiretrovirals and neutralizing antibodies [45,46]. In fact, opsonized HIV-1 particles accumulate in blood and lymphatic tissues among other complement-enriched compartments thus, providing several mechanisms for viral transmission [47]. Collectively, these information provides evidence about the possible mechanisms of how HIV-1 can escape the complement system and utilize it to invade other tissues which requires an important attention when considering complement system activation as a solid arm in management of HIV-1 infection. There are two types of antibodies that could develop during HIV-1 infection: neutralizing and non-neutralizing antibodies. After few weeks of HIV-1 infection or as less as 13 days, HIV-1 envelope-specific antibodies (non-neutralizing antibodies) start developing [48,49]. In fact, these antibodies amplify complement activation and deposition on viral envelope [50]. Even with this amplification after seroconversion, these antibodies however fail to induce complement mediated lysis of the infected cells or even the free virus due to the complement regulatory proteins [51]. Moreover, the presence of both complement and nonneutralizing anti-HIV antibodies that arise during the early phase

Please cite this article in press as: M.A.Y. Alqudah, et al., HIV-1 strategies to overcome the immune system by evading and invading innate immune system, HIV & AIDS Review (2015), http://dx.doi.org/10.1016/j.hivar.2015.07.004

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Fig. 1. Invasion and evasion of mucosal barriers and viral dissemination. During the early events after sexual transmission of the HIV-1, it faces a barrier of mucosal epithelial cells that may form a hurdle in the way of its invasion. However, the HIV-1 may cross this barrier, using many ways including: (1) transcytosis, (2) complement system, (3) DCs, or (4) damaged integrity of the mucosal epithelial cells. Now the virus can continue its journey to amplify its replication in the lymphoid tissues and spread to other organs initiating a systematic persistent infection. The main replicating site for the virus is the GALT, where a massive depletion of CD4+ T cells occur without being replenished from its differentiation sites mainly due to two reasons: (a) The dissemination of the HIV-1 to the BM and thymus (primary lymphoid organs) would affect the differentiation rate of T cells particularly, and other leukocytes generally resulting in pan-leukocytopenia. (b) The decreased expression of homing markers in GALT due to its damaged integrity. This damage would results in bacterial translocation initiating a systemic immune activation.

of infection have been shown to enhance viral infectivity through CRs up to 350-fold in some cases, as reported by Willey and coworkers [52]. Further, in the presence of complement proteins, anti-HIV antibodies confer higher HIV capture by erythrocytes than complement proteins alone which may further enhance the HIV dissemination [52,53]. On the other hand, neutralizing antibodies take several months up to years to be developed in HIV-1 infected individuals [54,55]. Of note, a small percentage of HIV-1 infected individuals are able to elicit such antibodies [56]. The question raised here is, do neutralizing antibodies provide a higher chance to induce

complement-mediated lysis than non-neutralizing antibodies? This question posed a real challenge in understanding the biology of HIV infection. Huber et al. [57] showed that monoclonal neutralizing antibodies such as 2F5, 4E10, and 2G12 have low activation of complement lysis activity compared to the activity of autologous polyclonal non-neutralizing antibodies. Earlier findings reported by Hessell and his colleagues [58] showed that monoclonal neutralizing antibody B12 display no complement activity in protecting Rhesus macaques against infection with Simian-Human Immunodeficiency Virus (SHIV), suggesting that polyclonal responses are more effective to induce the threshold of

Please cite this article in press as: M.A.Y. Alqudah, et al., HIV-1 strategies to overcome the immune system by evading and invading innate immune system, HIV & AIDS Review (2015), http://dx.doi.org/10.1016/j.hivar.2015.07.004

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complement cascade activation [57,58]. To further complicate the problem, recent published data have shown that complement system might efficiently participate in sterilizing immunity upon vaccination in animal model that mirrors for HIV-1 infection in humans [56]. In this study, it has been observed that, in the presence of complement proteins, the titers of serum neutralizing antibodies were higher in protected animals [59]. Taken together, these data indicate that complement system seems to be a doubleedged sword. Despite its important role in activating humoral immune response against HIV-1 infection, it is considered a bridge for HIV-1 trip toward target cells. Therefore, it is of particular importance to consider complement as an important component of the immune system especially when we talk about therapeutic or even protective vaccine strategies against HIV without excluding the other components of the immune system. Further studies are needed to investigate the impact of early inhibition of complement system on HIV-1 infectivity and disease progression. Moreover, other studies are needed to investigate the relationship of complement system with different newly identified neutralizing anti-HIV-1 antibodies to assess their ability to (1) induce the complement-mediated HIV-1 lysis and HIV-1-infected cell lysis, and (2) enhance the infectivity of HIV-1 toward cells that express CRs in order to abrogate this enhancement which may provide a real chance to avoid the HIV-1 circumvention of complement system. 3. Natural killer cells 3.1. NK cells and HIV-1 infection NK cells are large lymphocytes derived from hematopoietic stem cells in the bone marrow (BM), and constitute about 5–25% of the total circulating lymphocytes [60–62]. Similar to other immune cells, NK cells have the ability to migrate to various tissues in response to pro-inflammatory cytokine stimulation [60,63]. In fact, NK cells are heterogeneous cell population that are subdivided into two main subsets based on the expression of certain CD markers, particularly CD56 and CD16 [60]. The first subset is called CD56bright/CD16dim NK cells and the other one is called CD56dim/CD16bright NK cells [60]. CD56bright/CD16dim NK cells are predominant in the secondary lymphoid tissues accounting for about 90% of NK cells, characterized by their ability to secret large amounts of cytokines with limited cytotoxicity, whereas, CD56dim/CD16bright NK cells are highly cytotoxic and predominant in the systemic circulation [60]. NK cells are considered an essential effector arm of the innate immune system in boosting the adaptive immune response [6], tumor surveillance and being among the first lines of defense against viral infected cells including HIV-1 infection [62,64,65]. Indeed, NK cells express killer-cell immunoglobulin-like receptor (KIR) that recognize MHC class-I as an inhibitory signal of NK cell activation against normal/healthy cells and thus, NK cells only attack the cells that lack or have reduced MHC class-I expression on their surfaces such as malignant and viral infected cells [66– 68]. Cytotoxic NK cells mediate their cytotoxic effects on target cells via one of three mechanisms. First, NK cells are specialized in degranulation activating process in which they release their granular contents of perforin and granzymes toward target cells. This mechanism represents the main route of killing by NK cells [62]. Second, NK cells are able to induce apoptosis in target cells through several apoptotic signals such as Fas ligands and tumor necrosis factor (TNF)-related apoptosis inducing ligands (TRAIL) [69,70]. Finally, NK cells have the ability to secrete cytokines that could prevent viral replication [71] and upregulate major histocompatibility complex class-I (MHC class-I) expression on antigen presenting cells (APCs). Thus, this will enhance cytotoxic T cell recognition of infected cells [72].

Degranulation of cytotoxic granules of NK cells is triggered by engagement of antibody-coated cells with CD16 (FcgRIIIa) on NK cell surface, so-called, antibody-dependent cellular cytotoxicity (ADCC) [60]. In addition, it can be triggered by engagement of receptors on NK cells with their ligands on target cells [66,73]. These receptors include: (1) adhesion receptors, (2) activating receptors, and (3) co-activating receptors [67]. It is well-known that NK cell activation ensures selective killing of target cells leaving the healthy surrounding cells unharmed [66,67]. Therefore, the killing process by NK cells is tightly regulated by a balance of activating and inhibitory signals between NK cells and target cells, which determines whether NK cells become activated or not [74]. In addition to their role in immune surveillance and elimination of abnormal cells, NK cells play a critical role in the development of immune responses via cross-talk with DCs [75,76] and T cells [77]. In response to pathogens, DCs activate NK cells via secretion of IL-12 and IL-15, which in turn induce the maturation of antigenloaded DCs via secreting cytokines such as TNF-a and interferon-g (IFN-g) [75,76]. Consequently, mature DCs migrate into lymphoid tissues to activate effector cells of adaptive immune system [78]. In addition, NK cells participate in eliminating immature DCs that lack MHC class-I molecules on their surfaces [79]. The interaction of NK cell inhibitory (CD94/NKG2A) and activating (NKp30) receptors with DC’s corresponding ligands rely on the control of DCs by NK cells [79,80]. Thus, NK cells have a critical role in maturation of DCs and elimination of immature tolerogenic DCs. It is now clear that any defect or alteration in these immune cells can remarkably affect different immune responses. In this regard, we focused on the mechanisms that HIV-1 uses to escape and impair this component of the innate immune system, since this is the case in most HIV-1 infection subjects (HIV-1 progressors). 3.2. Role of HIV-1 evasion of NK cells As part of innate immune system, NK cells can effectively eliminate viral infected cells [48]. However, several studies have shown that many viruses including HIV-1 have evolved many mechanisms to evade the cytotoxic activity of NK cells [81,82], and even impair their function [83,84]. For instance, HIV-1 can alter the balance of activating and inhibitory receptors on NK cells by downregulating the expression of activating receptors on NK cells including NKp30, NKp44, NKp46 [84,85], and NKG2D [86]. In addition, HIV-1 is able to downregulate the expression of NK cell ligands on infected cells such as MHC class-I polypeptide-related sequence A (MICA), ULBP-1, ULBP-2 [87], and MHC class-I [88]. Moreover, the virus can upregulate the expression of inhibitory receptors including KIR [89]. Furthermore, HIV-1 infected individuals exhibit increased plasma soluble MICA, ULBP-2, and MHC class-I that could play as competitors with their corresponding receptors on NK cells and thus limiting the cytotoxic activation process [86]. However, none of these studies have estimated the prevalence and distribution of each mechanism among HIV-1 infected patients. As a result, correlation between each HIV-1 strategy to escape NK cell response and patient outcome will uncover whether these mechanism are worth to be further studied as targets for NK cell activation to eradicate HIV-1 infection. HIV-1 envelope glycoproteins Gp120 and Gp41 are usually found on the surface of productively (not latent) infected cells [90]. These glycoproteins are considered targets for antibody binding which triggers ADCC of NK cells via CD16 signaling [91]. The virus has evolved many mechanisms to circumvent the binding of anti-HIV envelope antibodies to infected cells such as: mutation of epitopes [92], masking of epitopes by heavy glycosylation of its glycoproteins [93] and by shedding of its

Please cite this article in press as: M.A.Y. Alqudah, et al., HIV-1 strategies to overcome the immune system by evading and invading innate immune system, HIV & AIDS Review (2015), http://dx.doi.org/10.1016/j.hivar.2015.07.004

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envelope glycoproteins [94]. Moreover, HIV-1 can reduce the expression of CD16 on the surface of NK cells through matrix metalloproteases (MMPs) [95], In line with these data, in an independent study, the levels of CD16 have been shown to be dramatically decreased in the sera of HIV-1 infected individuals when compared to healthy individuals, and have been shown to be associated with disease progression [39]. However, certain MMPs were shown to induce the shedding of CD16, thus producing soluble CD16 (sCD16) molecules that can act as competitors for ADCC [95]. Importantly, the sCD16 has also been shown to act as a natural ligand for CR3, and correlated with decreased viral dissemination through complement system [39]. Taken together, these data indicate that the expression of CD16 per cell is globally decreased, which in turn will negatively affects the levels of sCD16; since it has been shown that the source of sCD16 is the CD16 bearing cells. Moreover, the levels of sCD16 are consumed by either complement system or antibodies, which may further explain their depletion in the sera of HIV-1 patients. In addition to all strategies mentioned above, HIV-1 can escape the immune recognition by establishing a latent phase of cell infection. Interestingly, application of IL-12 and IFN-a has been shown to restore impaired NK cell ADCC in monkeys infected with SHIV and in vitro in human NK cells coated with HIV-1 [96,97]. Further in vivo preclinical and clinical studies are needed to evaluate the potential therapeutic effect of IL-12 and IFN-a in restoration of NK cell ADCC as a therapeutic modality in management of HIV-1 infection. Disease progression of HIV-1 infection has been reported as a result of dysfunctional NK cells [95,98], defects in cross-talk between NK cells and DCs [99] and by reduction of NK cell count along with expansion of an anergic CD56neg/CD16pos subset [100]. It has been proposed that the expansion of this anergic NK subset impairs all NK cell populations because these cells characterized by impaired cytokine secretion capacity and elevated levels of inhibitory receptors as well as reduced levels of activating receptors, and therefore play a critical role in the pathogenesis of HIV-1 infection [98,100,101]. However, these studies have not shown the mechanisms of expansion of anergic NK cells subset in HIV-1 infection, thereby additional investigations should be conducted to unravel these mechanisms. Subsequently, this may lead to better understanding of HIV-1 strategies to escape immune responses from one hand, and to develop new strategies that attempt to recover this population of cells on the other hand, and thus delay or even prevent disease progression. Since Jiang et al. [102] have recently shown that more preserved NK cell function is associated with delayed HIV-1 disease progression as seen in a minority of HIV-infected patients termed as long-term non-progressors (LTNP). Collectively, these findings reflect the severity of NK cell impairment in HIV-infection and AIDS patients. In addition, these findings indicate that NK cells are considered to be among the viral targets in which their impairment eventually affect the immune responses during the disease and participate in the development of malignancies seen in the late stages of disease. 4. Dendritic cells 4.1. Dendritic cells in HIV DCs are a heterogeneous cell population in the human body differentiated from more than one cell origin [103,104]. Hematopoietic progenitor cells in the BM and monocytes in periphery act as the main source for DC differentiation [103,104]. DCs are distributed in several tissues including mucosal surfaces, skin and systemic circulation making them among the first line cells that encounter pathogens [7,104]. Knowing that DCs are the most

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professional antigen-presenting cell (APC) among other APCs [7,103,105,106], they play a crucial role in bridging between innate and adaptive immune systems [7,105]. After capturing antigens in peripheral tissues, DCs migrate into lymphoid tissues where they present loaded antigens to T cells and shape the adaptive immune responses (discussed later) [107]. There is increasing evidence that DCs play a critical role in the pathophysiology of many infections and diseases. Increased or decreased DC count, impaired DC function and altered balance between DC subsets have been reported in different infections and pathological conditions [108–111]. Interestingly, it has been reported that HIV-1 infection is implicated in impairment of DCs functionally and numerically [112,113]. For these reasons, we focused our discussion in the next few sections on the role of DCs as principal effector cells of the immune system and as a direct or indirect target for HIV-1 and AIDS progression. 4.2. HlV-1 invasion and evasion of DCs HIV-1 can interact with DCs since they express different types of receptors on their surface such as CD4 [114], C-type lectin DC-specific intercellular adhesion molecule-3-rabbing nonintegrin (DC-SIGN) [115], langerin [116], and syndecan-3 [117]. Although the productive replication of DCs is relatively low compared to the more permissive types of cells, such as CD4+ T cells [118] and macrophages [119], DCs are severely affected in the course of HIV-1 infection. However, DCs are among the first line cells that encounter HIV-1 at mucosal surfaces after sexual transmission (Fig. 1). In fact, they are considered a double edge sword in both defense and transmission of HIV-1 infection. To get on the root of this infection, HIV-1 can harness the DCs as a vehicle to (1) cross the mucosal epithelial barrier, (2) infect bystander cells, and (3) to disseminate the virus into lymphoid tissues [120–123]. In addition, the major replication of HIV-1 occurs in lymphoid tissues due to the presence of a rich pool of target cells including the main target ‘‘CD4+ T cells’’ [124]. To ensure an efficient transmission of HIV-1 to T cells, portion of HIV-1 particles can evade the degradation by lysosomes and proteases of DCs, through routing HIV-1 into pocket-like compartments that maintain infectious HIV-1 particles for extended periods within DCs [125]. In fact, DCs can transfer HIV-1 to T cells through two different routes. The first one is mainly mediated by transinfection through the virological synapses or through exocytosis that is associated with HIV-1 exosomes [125,126]. On the other hand, the virus can be transmitted by cis-infection following de novo replication in DCs [127]. As expected, viral dissemination into several lymphoid tissues especially the gut-associated lymphoid tissue (GALT) leads to a massive depletion of CD4+ T cells [124,128]. As a result, propagation of persistent infection along with GALT damage leads eventually to bacterial translocation into the systemic circulation [120,129,130]. Finally, this leads to persistent systemic immune activation and enhancement of viral replication, two major hallmarks of disease progression (Fig. 1) [120,129,130]. These findings illustrate how this smart virus infects GALT and induces translocation of bacterial load from the lumen of gastrointestinal tract (GIT) into the blood which in turn can complicate the disease. Therefore, it is an important modality of choice to use therapeutic interventions such as sevelamer (phosphate binder used in kidney dialysis) that could block bacterial translocation as a strategy to reconstitute GIT mucosal immunity which may lead to lower the level of immune activation, and thus better control of HIV-1 disease progression. In human, there are two man distinct subsets of DCs that have been identified: myeloid dendritic cells (mDCs) and plasmacytoid dendritic cells (pDCs).

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4.3. Myeloid DCs Myeloid subset of DCs is best known for their ability to process and present antigens to T cells, beside their ability to secret cytokines [105]. In fact, they are distinguished from pDCs by expressing specific markers and Toll-Like Receptors (TLRs) (Table 1). They are also known as type 1 DC (DC1) according to their ability to trigger differentiation of helper T cells type 1 (Th1) by secreting high levels of IL-12 upon stimulation with TNF-a or CD40 ligand (CD40L) [131,132]. Thus, their impairment might affect different components of the immune system particularly adaptive responses. It has been demonstrated that HIV-1 impairs the function of mDCs as well as monocytes derived dendritic cells (MDDC) resulting in reducing the proper activation of other immune cells [133–135]. This defect includes impairing mDC ability to cross-talk with NK cells [99] and to present antigens to T cells due to the downregulation of MHC class-I and II expression on APCs (including DCs) by viral accessory protein known as negative factor (Nef) [136]. In addition, Nef modulates the expression of several essential receptors on the surface of infected cells that include: CD1, CD3, CD4, CD8, CD28, CD80, CD86, CCR5 and CXCR4 among other surface molecules which eventually leads to improper immune activation and enhanced viral replication [136]. Moreover, the virus may induce DC impairment and T cell exhaustion or tolerance by upregulating certain inhibitory receptors such as programmed death 1 and its ligand, and cytotoxic T-lymphocyte antigen 4 on DCs and T cells respectively, and thus disease progression [137–139]. Furthermore, the virus causes suboptimal-mature mDCs to accumulate in lymph nodes which have been implicated in induction of regulatory T (Treg) cells [140] that are well-known to suppress anti-HIV-1 immune response [141]. Interestingly, patients with depleted or low Treg cell count show greater anti-HIV-1 immune response compared with patients with higher Treg cell count [142]. In addition, elevated levels of histamine promote DCs to skew T cell differentiation into Treg cells and thus induction of immunosuppression in HIV-1 infected individuals [143,144]. In lines of these viral characteristics to evade mDCs, several studies have failed to show benefits of such therapeutic targets that could inhibit HIV-1 dissemination or induce anti-HIV-1 immune response. Although patients infected with Nef-deleted HIV-1 take longer time to progress to AIDS and a successful protective effect of dominantnegative Nef vaccine conferred to Rhesus macaques [145], recent studies have failed to show benefits of such vaccine in human [146]. In contrast, there was a 70% increase in the risk of HIV acquisition upon vaccination. Together, these data illustrate how the process of selecting therapeutic targets for HIV-1 treatment and prevention is challenging which requires further studies to identify other factors that interact with the known, available targets to increase the chance of therapeutic success. 4.4. Plasmacytoid DCs (pDCs) Plasmacytoid subset of DCs is best known for their ability to secret a huge amount of IFN-a up to 1000 folds higher than any other IFN-producing cell following viral infections [147]. PDCs do not efficiently present antigens to T cells as equal as mDCs do,

however, they are still considered as professional antigen presenting cells [106]. In fact, they are easily distinguished from mDCs based on morphology, specific surface markers and Toll-Like Receptors (TLRs) (Table 1). They are also known as Type 2 (DC2) according to their ability to trigger the differentiation of naive CD4+ T cells to type 2 helper T cells (Th2) in an IL-4 independent manner [148]. Similar to mDCs, pDCs are thought to play a critical role in innate immune response against many viruses including HIV-1 [149,150]. High levels of TLR7 and TLR9 have been shown to be expressed in pDCs, consequently, large amounts of IFN-a are produced upon activation of pDCs through TLR7 and TLR9 [151]. IFN-a interferes with viral replication and triggers APC maturation [152,153]. In addition, it inhibits HIV-1 replication in CD4+ T cells, macrophages, as well as DCs [154–156]. Moreover, it inhibits cell-to-cell transmission of the HIV-1 virus [122]. Consistent with these data, it has been shown that HIV-1 controllers (minority of HIV patients) have higher levels of IFN-a than viremic patients in their circulation [17]. Further, HIV-1 controllers show relatively preserved pDCs counts and function in their circulation indicating the important role of these cells as well as IFN-a in controlling the viral replication [17]. In fact, IFN-a has an adjuvant effects on different immune cells in addition to its role in DCs maturation [150,151]. Thus, any impairment in pDC function or reduction in their count might affect many vital roles of the immune system. On the other hand, several studies have shown that IFN-a contributes to chronic immune activation and depletion of bystander uninfected T cells [157,158] especially when comparing disease progression in females and males at the same level of viral replication [159]. Other studies have shown that pDCs activation in response to HIV-1 infection leads to production of indolemine 2,3-dioxygenase (IDO) which is associated with inverse outcomes such as dysfunctional T cells and induction of Treg cell [160]. Both cases are associated with limited anti-HIV-1 immune response, persistence viremia and disease progression [141]. Even with these conflicting findings, we still overbalance the critical role of pDCs in the course of HIV-1 infection. This discrepancy can be explained by the fact that high migration rate of pDCs into lymphoid tissues is associated with profound secretion of IFN-a that could lead to continuous tissue damage and killing of CD4+ T cell via TRAILexpressing pDCs that lead to disease progression [157,161]. In contrast, low migration rate of pDCs into lymphoid tissues preserves high IFN-a in systemic circulation and prevents lymphoid tissue damage as seen in the controllers. Generally speaking, HIV-1 infection is associated with both impaired function and reduced frequency of pDC count [113]. Obviously, it is well reported that the severity of DCs defects are more observed in advanced stages of HIV-1 infection [162]. These defects are also consistent with the higher viral load and thus disease progression [163]. These studies explain how pDCs are a doubleedged sword in which their depletion results in low immune response against HIV-1 represented by low IFN-a blood levels while their overactivation results in profound tissue damage due to high secretion level of IFN-a into peripheral tissues. In other words, when selecting pDCs and its IFN-a as a tool in treatment of HIV-1, it is of particular importance to consider the site of cell activation and cytokine secretion to obtain the optimal therapeutic effect and the least adverse events.

Table 1 mDCs and pDCs comparison.

mDCs pDCs

Surface markers

TLRs

Origin

References

CD11c, BDCA-1 CD123, BDCA-2, BDCA-4

TLR 1, 2, 3, 4, 5, 6, and 8 TLR 7 and 9

Myeloid progenitor cells Myeloid progenitor cells Lymphoid progenitor cells

[78,199,217] [217–219]

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4.5. Depletion of DCs in HIV infection Depletion of immune cells is another strategy for HIV-1 to overcome the immune system in the battle field. Depletion of both pDCs and mDCs from the circulation of HIV-1 infected patients has been reported by different groups [163,164]. This depletion could be explained by one of three possible mechanisms. First, direct infection with HIV-1 virus could lead to DCs apoptosis [163,164]. However, DCs are not the main target of the virus and thus the overall magnitude of DCs depletion from the circulation does not reflect their lower rate of infection with HIV-1, since it has been shown that HIV-1 infection of DCs is 10–100 times lower than CD4+ T cells [118,165]. Therefore, it is more likely to be explained by a second explanation, that is, increased migration rate of these cells into the lymphatic tissues. In fact, this migration is triggered upon the maturation of these cells by the virus itself or by lipopolysaccharides (LPS) after bacterial translocation to systemic circulation [130]. Several studies have demonstrated that pDCs in the circulation of HIV-1 patients significantly express higher levels of the lymph node homing markers CCR7 and CD62L [166,167], explaining the observation of Dillon et al. who failed to explain this homing [168]. Lehmann et al. [164] also have shown that pDCs express higher levels of CD103 in combination with integrin b7 mediating cell redistribution into GALT. However, Biancotto et al. [169] found that both pDCs and mDCs are dramatically depleted in lymph nodes of HIV-1 infected individuals with 40-fold (pDCs) and 20-fold (mDCs) less frequent compared to negative controls. These findings were later supported by Badolato et al. [170] observation of depleted pDCs levels in tonsils of HIV-1 infected children. This depletion could be explained by the rapid death of these cells upon their homing into lymph nodes [141,170]. Finally, the virus can affect hematopoiesis by infecting hematopoietic stem cells and common DCs progenitors in the BM resulting in pan-leukocytopenia and DC depletion in particular [171–173]. In addition, monocytes are considered a major source of DCs in human [7,104]. Therefore, the virus can infect monocyte-progenitors and induce apoptosis of monocytes, impair their differentiation to DCs by its Nef accessory protein [174,175] and eventually lead to DC depletion in HIV-1 infected individuals. Collectively, these studies illustrate how the virus acts on both central and peripheral arms of DC distribution and make the DCs are severely affected in the course of HIV-1 infection. Since we consider the DCs as a master of the immune system, we highlight the urgent need to restore their function and count (because these cells are usually depleted in these patients). In order to achieve this goal, we can induce the stem cell differentiation to a specific cell lineage (DCs in our case) in addition to the highly active antiretroviral therapy (HAART) to suppress HIV-1 replication along with antiinflammatory drugs to reduce the hyper-immune activation. Interestingly, all HIV-1 infected patients have hyperimmune activation thus we need to limit this activation which is believed to lead to disease progression by using commercially available antiinflammatory drugs. Eventually, this may lead to lower activation of DCs and preserve their count along with preserving the survival signals secreted by DCs to other immune cells which in turn delay or prevent disease progression. 5. Basophils and mast cells 5.1. Basophils and mast cells in HIV infection Basophils are the least (<1%) circulating granulated leukocytes that fully mature in the BM [8]. They could be found in peripheral tissues as a result of recruitment to the site of inflammation. Unlike basophils, mast cells are mainly found in peripheral tissues since they terminally mature after releasing from the BM [176]. Both

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types of cells are important effectors in IgE-mediated allergic inflammation, and they have the ability to shape the immune responses toward type 2 helper cells (Th2) in the absence of other stronger APCs such as DCs [8,177]. This could be due to their ability to secret type 2 cytokine signature such as IL-4 and IL-13. These cytokines induce differentiation of Th2 (but suppress Th2) and trigger humoral immune response marked by IgE antibody formation [178,179]. Elevation of IgE is coincident with histamine elevation that is released as a result of basophil or mast cell degranulation due to the cross linking of an allergen or antigen with IgE antibodies on FceRI on cell surface [180–182]. 5.2. Role of basophils and mast cells in HIV infection Early studies have found that HIV-1 patients have Th2 profile predominance over Th1 [183–185]. In contrast, others have failed to confirm this finding, and they have shown that HIV-1 favor the shift from Th1 to Th0 cells, they also have demonstrated that HIV-1 can efficiently replicate in Th2 as well as Th0 cells. Despite of this controversy, the early observations were confirmed by more recent studies that have shown an increase in production of IL-4, IL-10, IgE and histamine while decrease in the production of IL-2 and IFN-g which may confirm the shift of Th1 toward Th2 profile in these patients [186,187]. As discussed earlier, DCs are the main APCs that participate in the polarization of Th1 and Th2. In the absence of these cells, basophils and mast cells take a place in the polarization of Th2 in these patients [188]. This could be explained by several facts. Basophils and mast cells are able to secret IL-4 and IL-13 upon interaction of viral Gp120 with the IgE on their surfaces [189]. Alternatively, viral Gp41 and Tat are known to have chemoattractive properties for cells that express FceRI (basophils and mast cells) to the site of viral replication (lymphatic tissues) including GALT [190]. Moreover, these proteins can trigger the secretion of IL-4 and IL-13 by these cells [186]. Further, basophils and mast cells possess innate resistance against cytopathic effects by the HIV-1 infection providing evidence that these cells are not depleted and thus they participate in polarization of Th2 in HIV-1 infected individuals [191,192]. This polarization toward Th2 has been shown to be associated with the disease progression, in contrast to Th1 polarization which has been shown to be associated with long-term non-progressing disease status [193–196]. Hence, several vaccine strategies to maintain higher balance between Th1 and Th2 [194] or a skewed balance toward Th1 have been proposed [197,198]. In addition, if we take into consideration that basophils and mast cells can shape the subsequent adaptive immune responses in the absence of DCs, thus targeting basophils and mast cells for therapeutic strategy, or restoring the number and function of DCs in HIV-1 patients, both cases could lead to better control of HIV-1 infection. Mast cells can harbor the virus (in a latent phase) for a long time since they are originally long lived cells and the virus has no cytopathic effects on these cells [191,192]. Moreover, mast cells are distributed in various compartments of the body including the GALT where the main replication of HIV-1 occurs [124,190]. These data strongly suggest that these cells participate in the persistence of the virus and disease progression in these patients. Collectively, basophils and mast cells have been poorly studied compared to other cells (discussed above), although they have been considered as one of the obstacles that may prevent the eradication of the virus from these patients even under treatment with HAART by sustaining a pool of long lived latent infected cells. Thus, future studies are needed to study the mechanisms of latency in these cells which may help to develop strategies that allow the reactivation of these latent cells which potentially could lead to partial eradication of the virus from these patients and complete eradication when all latently infected cells are activated.

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6. Monocytes and macrophages

7. Conclusions

6.1. Monocytes and macrophages in HIV infection

HIV-1 infection is a common disease worldwide with grim outcome and less than optimal therapy. Although several studies have implicated adaptive immunity as the main target to activate immune system against HIV-1 infection, a bulk of evidence indicates that innate immunity could be considered a cornerstone target for HIV-1 infection and, if reactivated, an important arm to prevent disease progression. The impact of early inhibition of complement system on HIV-1 infectivity and disease progression and the mechanisms of expansion of anergic NK cells subset need to be further studied. In addition, modulation of specific members of innate immunity can be foreseen as a promising strategy in patients with HIV-1 infection. In particular, the use of certain cytokines (such as IL-12 and IFN-a) in restoration of NK cell ADCC, the use of therapeutic interventions (such as sevelamer) that block bacterial translocation to reconstitute GIT mucosal immunity, reactivation of latent infected cells, studying the use of anti-HIVaccessory protein antibodies (such as anti-Nef and -Tat antibodies) and investigating the mechanisms of failure in HIV vaccination. Hence, we hypothesize that activating or targeting certain members/molecules of innate immunity via several strategies may improve therapeutic outcome in the treatment of HIV-1 infection.

Monocytes are heterogeneous cells derived from hematopoietic stem cells in the BM where they circulate for few days before their differentiation into macrophages or DCs in peripheral tissues to [103]. Monocytes play a critical role in the defense against pathogens [199]. Macrophages are long-lived terminally differentiated phagocytes capable of eliminating pathogens and activating the adaptive immune response as an APC in addition to their role in homeostasis [9]. Monocytes/macrophages play a critical role during the course of HIV-1 infection, since they can harbor the virus for a long period of time. 6.2. HIV invasion and evasion of monocytes and macrophages It is well known that monocyte/macrophage lineage is among the earliest cells that become infected with HIV-1 (Fig. 1). They represent an important target and source of the virus during the course of HIV-1 infection [200]. It is also well-established that monocytes are relatively resistant to HIV-1 compared with macrophages [201]. However, infected monocytes have been reported in HIV-1 infected patients even with HAART [200–202]. Therefore, monocytes are considered as a critical arm that participates in the persistence of infection during the HIV-1 course. After dissemination of the HIV-1 into the BM, HIV-1 usually uses monocytes as a vehicle to disseminate into systemic circulation and other tissues including central nervous system (CNS) [170,203]. In fact, infected monocytes can cross the blood brain barrier more efficiently than non-infected monocytes [167,204] facilitating the initiation of persistent infection in the CNS [205]. Moreover, infected circulating monocytes are recruited to the intestinal tissues which are favorable sites for HIV-1 replication, spread, and persistence [206]. Here, they differentiate into macrophages and result in establishing an HIV-1 reservoir [207]. Interestingly, these persistent infected cells are one of the most important obstacles to eradicate the virus from these infected individuals after the era of antiretroviral therapy. The virus has evolved many strategies to escape the internal endosomal compartments of macrophages and other APCs (discussed earlier) [207]. It has been postulated that the HIV-1 can be transmitted in term of cell-to-cell (trans-infection) more efficiently than free virus-to-cell (cis-infection), using virological synapses [208] or tunneling nanotubes [209]. Thus, the virus establishes a route to circumvent the humoral immune responses of both innate and adaptive immune systems. HIV-1 can evade our immune system using its accessory proteins. One such protein is Nef which is one of the most pathogenic viral proteins that participate in the pathogenesis and progression to AIDS [134,210]. Nef could be found soluble in the sera of HIV-1 infected individuals. Nef has been shown to enter macrophages [211] which can downregulate the expression of many cellular proteins and interfere with many cellular functions resulting in cellular impairment and disease progression [212]. Tat is another viral protein which also could be detected in the sera of HIV-1 infected individuals, which has been shown to promote HIV1 infection of monocytes/macrophages [213]. It has been reported that Tat induces the secretion of soluble (TRAIL) in human macrophages, leading to the death of bystander CD4+ T lymphocytes [214] thus promoting disease progression. Here we propose to use anti-HIV-accessory protein antibodies such as anti-Nef and Tat antibodies in particular. This may lead to the design of new therapeutic strategies to delay disease progression in patients with HIV infection [215,216].

Conflict of interest None declared. Financial disclosure None declared. References [1] J.A. Levy, A.D. Hoffman, S.M. Kramer, J.A. Landis, J.M. Shimabukuro, et al., Isolation of lymphocytopathic retroviruses from San Francisco patients with AIDS, Science 225 (1984) 840–842. [2] UNAIDS, World AIDS Day 2014 Report – Fact Sheet, 2014, http://www.unaids. org/en/resources/campaigns/World-AIDS-Day-Report-2014/factsheet. [3] H. Xu, X. Wang, R.S. Veazey, Mucosal immunology of HIV infection, Immunol. Rev. 254 (2013) 10–33. [4] B. Ensoli, A. Cafaro, P. Monini, S. Marcotullio, F. Ensoli, Challenges in HIV vaccine research for treatment and prevention, Front. Immunol. 5 (2014) 417. [5] I. Klaska, J.Z. Nowak, The role of complement in physiology and pathology, Postep. Hig. Med. Dosw. 61 (2007) 167–177. [6] R.B. Mailliard, Y.I. Son, R. Redlinger, P.T. Coates, A. Giermasz, et al., Dendritic cells mediate NK cell help for Th1 and CTL responses: two-signal requirement for the induction of NK cell helper function, J. Immunol. 171 (2003) 2366–2373. [7] R. Kushwah, J. Hu, Complexity of dendritic cell subsets and their function in the host immune system, Immunology 133 (2011) 409–419. [8] B.M. Sullivan, R.M. Locksley, Basophils: a nonredundant contributor to host immunity, Immunity 30 (2009) 12–20. [9] J. Jantsch, K.J. Binger, D.N. Muller, J. Titze, Macrophages in homeostatic immune function, Front. Physiol. 5 (2014) 146. [10] J.A. Levy, The importance of the innate immune system in controlling HIV infection and disease, Trends Immunol. 22 (2001) 312–316. [11] P. Borrow, R.J. Shattock, A. Vyakarnam, EUROPRISE Working Group, Innate immunity against HIV: a priority target for HIV prevention research, Retrovirology 7 (2010) 84. [12] R. Ellega˚rd, E.M. Shankar, M. Larsson, Targeting HIV-1 innate immune responses therapeutically, Curr. Opin. HIV AIDS 6 (2011) 435–443. [13] E.M. Shankar, V. Velu, R. Vignesh, S. Vijayaraghavalu, D.V. Rukumani, N.S. Sabet, Recent advances targeting innate immunity-mediated therapies against HIV-1 infection, Microbiol. Immunol. 56 (2012) 497–505. [14] A. Sa´ez-Cirio´n, C. Hamimi, A. Bergamaschi, A. David, P. Versmisse, et al., Restriction of HIV-1 replication in macrophages and CD4+ T cells from HIV controllers, Blood 118 (2011) 955–964. [15] F. Marras, E. Nicco, F. Bozzano, A. Di Biagio, C. Dentone, et al., Natural killer cells in HIV controller patients express an activated effector phenotype and do not upregulate NKp44 on IL-2 stimulation, Proc. Natl. Acad. Sci. U. S. A. 110 (2013) 11970–11975. [16] S. Krishnan, E.M. Wilson, V. Sheikh, A. Rupert, D. Mendoza, et al., Evidence for innate immune system activation in HIV type 1-infected elite controllers, J. Infect. Dis. 209 (2014) 931–939.

Please cite this article in press as: M.A.Y. Alqudah, et al., HIV-1 strategies to overcome the immune system by evading and invading innate immune system, HIV & AIDS Review (2015), http://dx.doi.org/10.1016/j.hivar.2015.07.004

G Model

HIVAR-131; No. of Pages 12 M.A.Y. Alqudah et al. / HIV & AIDS Review xxx (2015) xxx–xxx [17] K. Machmach, M. Leal, C. Gras, P. Viciana, M. Genebat, et al., Plasmacytoid dendritic cells reduce HIV production in elite controllers, J. Virol. 86 (2012) 4245–4252. [18] C. Tomescu, Q. Liu, B.N. Ross, X. Yin, K. Lynn, et al., A correlate of HIV-1 control consisting of both innate and adaptive immune parameters best predicts viral load by multivariable analysis in HIV-1 infected viremic controllers and chronically-infected non-controllers, PLOS ONE 9 (2014) e103209. [19] F.R. Toapanta, T.M. Ross, Complement-mediated activation of the adaptive immune responses: role of C3d in linking the innate and adaptive immunity, Immunol. Res. 36 (2006) 197–210. [20] D. Ricklin, G. Hajishengallis, K. Yang, J.D. Lambris, Complement: a key system for immune surveillance and homeostasis, Nat. Immunol. 11 (2010) 785–797. [21] X. Qin, B. Gao, The complement system in liver diseases, Cell. Mol. Immunol. 3 (2006) 333–340. [22] A. Kojima, K. Iwata, T. Seya, M. Matsumoto, H. Ariga, et al., Membrane cofactor protein (CD46) protects cells predominantly from alternative complement pathway-mediated C3-fragment deposition and cytolysis, J. Immunol. 151 (1993) 1519–1527. [23] S. Rollins, P. Sims, The complement-inhibitory activity of CD59 resides in its capacity to block incorporation of C9 into membrane C5b-9, J. Immunol. 144 (1990) 3478–3483. [24] T. Fujita, T. Inoue, K. Ogawa, K. Iida, N. Tamura, The mechanism of action of decay-accelerating factor (DAF). DAF inhibits the assembly of C3 convertases by dissociating C2a and Bb, J. Exp. Med. 166 (1987) 1221–1228. [25] T. Seya, L.L. Ballard, N.S. Bora, V. Kumar, W. Cui, et al., Distribution of membrane cofactor protein of complement on human peripheral blood cells. An altered form is found on granulocytes, Eur. J. Immunol. 18 (1993) 1289–1294. [26] L.W. Terstappen, M. Nguyen, H.M. Lazarus, M.E. Medof, Expression of the DAF (CD55) and CD59 antigens during normal hematopoietic cell differentiation, J. Leukoc. Biol. 52 (1992) 652–660. [27] J.M. Weiler, M.R. Daha, K.F. Austen, D.T. Fearon, Control of the amplification convertase of complement by the plasma protein beta1H, Proc. Natl. Acad. Sci. U. S. A. 73 (1976) 3268–3272. [28] K. Broliden, Innate molecular and anatomic mucosal barriers against HIV infection in the genital tract of HIV-exposed seronegative individuals, J. Infect. Dis. 202 (Suppl. 3) (2010) S351–S355. [29] H. Bouhlal, N. Chomont, N. Haeffner-Cavaillon, M.D. Kazatchkine, L. Belec, et al., Opsonization of HIV-1 by semen complement enhances infection of human epithelial cells, J. Immunol. 169 (2002) 3301–3306. [30] C.F. Ebenbichler, N.M. Thielens, R. Vornhagen, S. Marschang, G.J. Arlaud, et al., Human immunodeficiency virus type 1 activates the classical pathway of complement by direct C1 binding through specific sites in the transmembrane glycoprotein gp41, J. Exp. Med. 174 (1991) 1417–1424. [31] X. Ji, H. Gewurz, G.T. Spear, Mannose binding lectin (MBL) and HIV, Mol. Immunol. 42 (2005) 145–152. [32] B.L. Sullivan, E.J. Knopoff, M. Saifuddin, D.M. Takefman, M.N. Saarloos, et al., Susceptibility of HIV-1 plasma virus to complement-mediated lysis. Evidence for a role in clearance of virus in vivo, J. Immunol. 157 (1996) 1791–1798. [33] V. Tjomsland, R. Ellegard, A. Burgener, K. Mogk, K.F. Che, et al., Complement opsonization of HIV-1 results in a different intracellular processing pattern and enhanced MHC class I presentation by dendritic cells, Eur. J. Immunol. 43 (2013) 1470–1483. [34] R. Ellega˚rd, E. Crisci, A. Burgener, C. Sjo¨wall, K. Birse, et al., Complement opsonization of HIV-1 results in decreased antiviral and inflammatory responses in immature dendritic cells via CR3, J. Immunol. 193 (2014) 4590–4601. [35] M. Saifuddin, T. Hedayati, J.P. Atkinson, M.H. Holguin, C.J. Parker, et al., Human immunodeficiency virus type 1 incorporates both glycosyl phosphatidylinositol-anchored CD55 and CD59 and integral membrane CD46 at levels that protect from complement-mediated destruction, J. Gen. Virol. 78 (1997) 1907–1911. [36] I. Frank, H. Stoiber, S. Godar, H. Stockinger, F. Steindl, et al., Acquisition of host cell-surface-derived molecules by HIV-1, AIDS 10 (1996) 1611–1620. [37] H. Stoiber, C. Pinter, A.G. Siccardi, A. Clivio, M.P. Dierich, Efficient destruction of human immunodeficiency virus in human serum by inhibiting the protective action of complement factor H and decay accelerating factor (DAF, CD55), J. Exp. Med. 183 (1996) 307–310. [38] P.K. Datta, J. Rappaport, HIV and complement: hijacking an immune defense, Biomed. Pharmacother. 60 (2006) 561–568. [39] H. Bouhlal, J. Galon, M.D. Kazatchkine, W.H. Fridman, C. Sautes-Fridman, et al., Soluble CD16 inhibits CR3 (CD11b/CD18)-mediated infection of monocytes/macrophages by opsonized primary R5 HIV-1, J. Immunol. 166 (2001) 3377–3383. [40] H. Bouhlal, N. Chomont, M. Requena, N. Nasreddine, H. Saidi, et al., Opsonization of HIV with complement enhances infection of dendritic cells and viral transfer to CD4 T cells in a CR3 and DC-SIGN-dependent manner, J. Immunol. 178 (2007) 1086–1095. [41] C.C. Delibrias, A. Mouhoub, E. Fischer, M.D. Kazatchkine, CR1(CD35) and CR2(CD21) complement C3 receptors are expressed on normal human thymocytes and mediate infection of thymocytes with opsonized human immunodeficiency virus, Eur. J. Immunol. 24 (1994) 2784–2788. [42] C. Hess, T. Klimkait, L. Schlapbach, V. Del Zenero, S. Sadallah, et al., Association of a pool of HIV-1 with erythrocytes in vivo: a cohort study, Lancet 359 (2002) 2230–2234. [43] S. Moir, A. Malaspina, Y. Li, T.-W. Chun, T. Lowe, et al., B cells of HIV-1-infected patients bind virions through CD21-complement interactions and transmit infectious virus to activated T cells, J. Exp. Med. 192 (2000) 637–646.

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[44] B.F. Keele, L. Tazi, S. Gartner, Y. Liu, T.B. Burgon, et al., Characterization of the follicular dendritic cell reservoir of HIV-1, J. Virol. 82 (2008) 5548–5561. [45] R. Tsunoda, K. Hashimoto, M. Baba, S. Shigeta, N. Sugai, Follicular dendritic cells in vitro are not susceptible to infection by HIV-1, AIDS 10 (1996) 595–602. [46] J. Schmitz, J.v. Lunzen, K. Tenner-Racz, G. Grossschupff, P. Racz, et al., Follicular dendritic cells retain HIV-1 particles on their plasma membrane, but are not productively infected in asymptomatic patients with follicular hyperplasia, J. Immunol. 153 (1994) 1352–1359. [47] H. Stoiber, Z. Banki, D. Wilflingseder, M.P. Dierich, Complement–HIV interactions during all steps of viral pathogenesis, Vaccine 26 (2008) 3046–3054. [48] G.D. Tomaras, N. Yates, P. Liu, L. Qin, G. Fouda, et al., Initial B cell responses to transmitted HIV-1: virion-binding IgM and IgG antibodies followed by plasma anti-gp41 antibodies with ineffective control of initial viremia, J. Virol. 82 (2008) 12449–12463. [49] G.D. Tomaras, B.F. Haynes, HIV-1-specific antibody responses during acute and chronic HIV-1 infection, Curr. Opin. HIV AIDS 4 (2009) 373–379. [50] G.T. Spear, D.M. Takefman, B.L. Sullivan, A.L. Landay, S. Zolla-Pazner, Complement activation by human monoclonal antibodies to human immunodeficiency virus, J. Virol. 67 (1993) 53–59. [51] J. Schmitz, J.P. Zimmer, B. Kluxen, S. Aries, M. Bo¨gel, et al., Antibody-dependent complement-mediated cytotoxicity in sera from patients with HIV-1 infection is controlled by CD55 and CD59, J. Clin. Investig. 96 (1995) 1520–1526. [52] S. Willey, M.M. Aasa-Chapman, S. O’Farrell, P. Pellegrino, I. Williams, et al., Extensive complement-dependent enhancement of HIV-1 by autologous nonneutralising antibodies at early stages of infection, Retrovirology 8 (2011). [53] M.N. Garcia, M.S. dos Ramos Farias, L. Fazzi, D. Grasso, R.D. Rabinovich, et al., Presence of IgG anti-gp160/120 antibodies confers higher HIV capture capacity to erythrocytes from HIV-positive individuals, PLoS ONE 7 (2012) e45808. [54] Y. Li, K. Svehla, M.K. Louder, D. Wycuff, S. Phogat, et al., Analysis of neutralization specificities in polyclonal sera derived from human immunodeficiency virus type 1-infected individuals, J. Virol. 83 (2009) 1045–1059. [55] L. Stamatatos, L. Morris, D.R. Burton, J.R. Mascola, Neutralizing antibodies generated during natural HIV-1 infection: good news for an HIV-1 vaccine? Nat. Med. 15 (2009) 866–870. [56] L.M. Walker, M.D. Simek, F. Priddy, J.S. Gach, D. Wagner, et al., A limited number of antibody specificities mediate broad and potent serum neutralization in selected HIV-1 infected individuals, PLoS Pathog. 6 (2010) e1001028. [57] M. Huber, V.v. Wyl, C.G. Ammann, H. Kuster, G. Stiegler, et al., Potent human immunodeficiency virus-neutralizing and complement lysis activities of antibodies are not obligatorily linked, J. Virol. 82 (2008) 3834–3842. [58] A.J. Hessell, L. Hangartner, M. Hunter, C.E.G. Havenith, F.J. Beurskens, et al., Fc receptor but not complement binding is important in antibody protection against HIV, Nature 449 (2007) 101–104. [59] M. Page, R. Quartey-Papafio, M. Robinson, M. Hassall, M. Cranage, et al., Complement-mediated virus infectivity neutralisation by HLA antibodies is associated with sterilising immunity to SIV challenge in the macaque model for HIV/ AIDS, PLOS ONE 9 (2014) e88735. [60] M.A. Cooper, T.A. Fehniger, M.A. Caligiuri, The biology of human natural killercell subsets, Trends Immunol. 22 (2001) 633–640. [61] A. Moretta, C. Bottino, M.C. Mingari, R. Biassoni, L. Moretta, What is a natural killer cell, Nat. Immunol. 3 (2002) 6–8. [62] M.A. Caligiuri, Human natural killer cell, Blood 112 (2008) 461–469. [63] A.A. Maghazachi, Compartmentalization of human natural killer cells, Mol. Immunol. 42 (2005) 523–529. [64] L.L. Lanier, Evolutionary struggles between NK cells and viruses, Nat. Rev. Immunol. 8 (2008) 259–268. [65] S. Jost, M. Altfeld, Control of human viral infections by natural killer cells, Annu. Rev. Immunol. 31 (2013) 163–194. [66] L.L. Lanier, NK cell recognition, Annu. Rev. Immunol. 23 (2005) 225–274. [67] Y.T. Bryceson, M.E. March, H.G. Ljunggren, E.O. Long, Activation, coactivation, and costimulation of resting human natural killer cells, Immunol. Rev. 214 (2006) 73–91. [68] M.A. Ivarsson, J. Michaelsson, C. Fauriat, Activating killer cell Ig-like receptors in health and disease, Front. Immunol. 5 (2014) 184. [69] H. Arase, N. Arase, T. Saito, Fas-mediated cytotoxicity by freshly isolated natural killer cells, J. Exp. Med. 181 (1995) 1235–1238. [70] L. Zamai, M. Ahmad, I.M. Bennett, L. Azzoni, E.S. Alnemri, et al., Natural killer (NK) cell-mediated cytotoxicity: differential use of TRAIL and Fas ligand by immature and mature primary human NK cells, J. Exp. Med. 188 (1998) 2375–2380. [71] E.M. Bluman, K.J. Bartynski, B.R. Avalos, M.A. Caligiuri, Human natural killer cells produce abundant macrophage inflammatory protein-1 alpha in response to monocyte-derived cytokines, J. Clin. Investig. 97 (1996) 2722–2727. [72] R. Mocikat, H. Braumuller, A. Gumy, O. Egeter, H. Ziegler, et al., Natural killer cells activated by MHC class I (low) targets prime dendritic cells to induce protective CD8 T cell responses, Immunity 19 (2003) 561–569. [73] L.L. Lanier, Up on the tightrope: natural killer cell activation and inhibition, Nat. Immunol. 9 (2008) 495–502. [74] R. Biassoni, Human natural killer receptors, co-receptors, and their ligands, Curr. Protoc. Immunol. (2009), Chapter 14: Unit 14.10. [75] T. Walzer, M. Dalod, E. Vivier, L. Zitvogel, Natural killer cell-dendritic cell crosstalk in the initiation of immune responses, Expert Opin. Biol. Ther. 5 (Suppl. 1) (2005) S49–S59. [76] G. Ferlazzo, Natural killer and dendritic cell liaison: recent insights and open questions, Immunol. Lett. 101 (2005) 12–17. [77] S.N. Waggoner, M. Cornberg, L.K. Selin, R.M. Welsh, Natural killer cells act as rheostats modulating antiviral T cells, Nature 481 (2011) 394–398.

Please cite this article in press as: M.A.Y. Alqudah, et al., HIV-1 strategies to overcome the immune system by evading and invading innate immune system, HIV & AIDS Review (2015), http://dx.doi.org/10.1016/j.hivar.2015.07.004

G Model

HIVAR-131; No. of Pages 12 10

M.A.Y. Alqudah et al. / HIV & AIDS Review xxx (2015) xxx–xxx

[78] J. Banchereau, R.M. Steinman, Dendritic cells and the control of immunity, Nature 392 (1998) 245–252. [79] M.D. Chiesa, M. Vitale, S. Carlomagno, G. Ferlazzo, L. Moretta, et al., The natural killer cell-mediated killing of autologous dendritic cells is confined to a cell subset expressing CD94/NKG2A, but lacking inhibitory killer Ig-like receptors, Eur. J. Immunol. 33 (2003) 1657–1666. [80] M. Vitale, M.D. Chiesa, S. Carlomagno, D. Pende, M. Arico`, et al., NK-dependent DC maturation is mediated by TNFalpha and IFNgamma released upon engagement of the NKp30 triggering receptor, Blood 106 (2005) 566–571. [81] S. Jonjic, M. Babic, B. Polic, A. Krmpotic, Immune evasion of natural killer cells by viruses, Curr. Opin. Immunol. 20 (2008) 30–38. [82] S. Jost, M. Altfeld, Evasion from NK cell-mediated immune responses by HIV-1, Microbes Infect. 14 (2012) 904–915. [83] V. Naranbhai, M. Altfeld, S.S. Karim, T. Ndung’u, Q.A. Karim, et al., Changes in natural killer cell activation and function during primary HIV-1 infection, PLOS ONE 8 (2013) e53251. [84] A.H.W. Wong, K. Williams, S. Reddy, D. Wilson, J. Giddy, et al., Alterations in natural killer cell receptor profiles during HIV type 1 disease progression among chronically infected South African adults, AIDS Res. Hum. Retrovir. 26 (2010) 459–469. [85] A.D. Maria, M. Fogli, P. Costa, G. Murdaca, F. Puppo, et al., The impaired NK cell cytolytic function in viremic HIV-1 infection is associated with a reduced surface expression of natural cytotoxicity receptors (NKp46, NKp30 and NKp44), Eur. J. Immunol. 33 (2003) 2410–2418. [86] G. Matusali, H.K. Tchidjou, G. Pontrelli, S. Bernardi, G. D’Ettorre, et al., Soluble ligands for the NKG2D receptor are released during HIV-1 infection and impair NKG2D expression and cytotoxicity of NK cells, FASEB J. 27 (2013) 2440–2450. [87] C. Cerboni, F. Neri, N. Casartelli, A. Zingoni, D. Cosman, et al., Human immunodeficiency virus 1 Nef protein downmodulates the ligands of the activating receptor NKG2D and inhibits natural killer cell-mediated cytotoxicity, J. Gen. Virol. 88 (2007) 242–250. [88] F. Puppo, S. Brenci, L. Lanza, O. Bosco, M.A. Imro, et al., Increased level of serum HLA class I antigens in HIV infection. Correlation with disease progression, Hum. Immunol. 40 (1994) 259–266. [89] P. Andre, C. Brunet, S. Guia, H. Gallais, J. Sampol, et al., Differential regulation of killer cell Ig-like receptors and CD94 lectin-like dimers on NK and T lymphocytes from HIV-1-infected individuals, Eur. J. Immunol. 29 (1999) 1076–1085. [90] R. Wyatt, J. Sodroski, The HIV-1 envelope glycoproteins: fusogens, antigens, and immunogens, Science 280 (1998) 1884–1888. [91] E. Vivier, E. Tomasello, M. Baratin, T. Walzer, S. Ugolin, Functions of natural killer cells, Nat. Immunol. 9 (2008) 503–510. [92] L. Rezende, Y. Kew, V. Prasad, The effect of increased processivity on overall fidelity of human immunodeficiency virus type 1 reverse transcriptase, J. Biomed. Sci. 8 (2001) 197–205. [93] J.N. Reitter, R.E. Means, R.C. Desrosiers, A role for carbohydrates in immune evasion in AIDS, Nat. Med. 4 (1998) 679–684. [94] P.W. Parren, J.P. Moore, D.R. Burton, Q.J. Sattentau, The neutralizing antibody response to HIV-1: viral evasion and escape from humoral immunity, AIDS 13 (Suppl. A) (1999) S137–S162. [95] Q. Liu, Y. Sun, S. Rihn, A. Nolting, P.N. Tsoukas, et al., Matrix metalloprotease inhibitors restore impaired NK cell-mediated antibody-dependent cellular cytotoxicity in human immunodeficiency virus type 1 infection, J. Virol. 83 (2009) 8705–8712. [96] Q.H. Nguyen, R.L. Roberts, B.J. Ank, S.J. Lin, C.K. Lau, E.R. Stiehm, Enhancement of antibody-dependent cellular cytotoxicity of neonatal cells by interleukin-2 (IL2) and IL-12, Clin. Diagn. Lab. Immunol. 5 (1998) 98–104. [97] V. Poaty-Mavoungou, F.S. Toure´, C. Tevi-Benissan, E. Mavoungou, Enhancement of natural killer cell activation and antibody-dependent cellular cytotoxicity by interferon-alpha and interleukin-12 in vaginal mucosae Sivmac251-infected Macaca fascicularis, Viral Immunol. 15 (2002) 197–212. [98] G. Alter, N. Teigen, B.T. Davis, M.M. Addo, T.J. Suscovich, et al., Sequential deregulation of NK cell subset distribution and function starting in acute HIV-1 infection, Blood 106 (2005) 3366–3369. [99] M. Altfeld, L. Fadda, D. Frleta, N. Bhardwaj, DCs and NK cells: critical effectors in the immune response to HIV-1, Nat. Rev. Immunol. 11 (2011) 176–186. [100] J.M. Milush, S. Lopez-Verges, V.A. York, S.G. Deeks, J.N. Martin, et al., CD56negCD16(+) NK cells are activated mature NK cells with impaired effector function during HIV-1 infection, Retrovirology 10 (2013) 158. [101] D. Mavilio, G. Lombardo, J. Benjamin, D. Kim, D. Follman, et al., Characterization of CD56 /CD16+ natural killer (NK) cells: a highly dysfunctional NK subset expanded in HIV-infected viremic individuals, Proc. Natl. Acad. Sci. U. S. A. 102 (2005) 2886–2891. [102] Y. Jiang, F. Zhou, Y. Tian, Z. Zhang, R. Kuang, et al., Higher NK cell IFN-g production is associated with delayed HIV disease progression in LTNPs, J. Clin. Immunol. 33 (2013) 1376–1385. [103] F. Geissmann, M.G. Manz, S. Jung, M.H. Sieweke, M. Merad, et al., Development of monocytes, macrophages, and dendritic cells, Science 327 (2010) 656–661. [104] J. Idoyaga, R.M. Steinman, SnapShot: dendritic cells, Cell 146 (2011), 660–660.e2. [105] I. Mellman, R.M. Steinman, Dendritic cells: specialized and regulated antigen processing machines, Cell 106 (2001) 255–258. [106] J. Tel, A.M.v.d. Leun, C.G. Figdor, R. Torensma, I.J.M.d. Vries, Harnessing human plasmacytoid dendritic cells as professional APCs, Cancer Immunol. Immunother. 61 (2012) 1279–1288. [107] R. Steinman, Linking innate to adaptive immunity through dendritic cells, Novartis Found. Symp. 279 (2006) 101–109.

[108] P. Middel, D. Raddatz, B. Gunawan, F. Haller, H.-J. Radzun, Increased number of mature dendritic cells in Crohn’s disease: evidence for a chemokine mediatedretention mechanism, Gut 55 (2006) 220–227. [109] R. Ciccocioppo, G. Ricci, B. Rovati, I. Pesce, S. Mazzocchi, et al., Reduced number and function of peripheral dendritic cells in coeliac disease, Clin. Exp. Immunol. 149 (2007) 487–496. [110] T. Kanto, M. Inoue, H. Miyatake, A. Sato, M. Sakakibara, et al., Reduced numbers and impaired ability of myeloid and plasmacytoid dendritic cells to polarize T helper cells in chronic hepatitis C virus infection, J. Infect. Dis. 190 (2004) 1919–1926. [111] H. Matsuda, T. Suda, H. Hashizume, K. Yokomura, K. Asada, et al., Alteration of balance between myeloid dendritic cells and plasmacytoid dendritic cells in peripheral blood of patients with asthma, Am. J. Respir. Crit. Care Med. 166 (2002) 1050–1054. [112] F. Grassi, A. Hosmalin, D. McIlroy, V. Calvez, P. Debre, et al., Depletion in blood CD11c-positive dendritic cells from HIV-infected patients, AIDS 13 (1999) 759–766. [113] S. Feldman, D. Stein, S. Amrute, T. Denny, Z. Garcia, et al., Decreased interferonalpha production in HIV-infected patients correlates with numerical and functional deficiencies in circulating type 2 dendritic cell precursors, Clin. Immunol. 101 (2001) 201–210. [114] S.G. Turville, P.U. Cameron, A. Handley, G. Lin, S. Pohlmann, et al., Diversity of receptors binding HIV on dendritic cell subsets, Nat. Immunol. 3 (2002) 975–983. [115] J.F. Arrighi, M. Pion, M. Wiznerowicz, T.B. Geijtenbeek, E. Garcia, et al., Lentivirus-mediated RNA interference of DC-SIGN expression inhibits human immunodeficiency virus transmission from dendritic cells to T cells, J. Virol. 78 (2004) 10848–10855. [116] L.d. Witte, A. Nabatov, M. Pion, D. Fluitsma, M.A.W.P.d. Jong, et al., Langerin is a natural barrier to HIV-1 transmission by Langerhans cells, Nat. Med. 13 (2007) 367–371. [117] L.d. Witte, M. Bobardt, U. Chatterji, G. Degeest, G. David, et al., Syndecan-3 is a dendritic cell-specific attachment receptor for HIV-1, Proc. Natl. Acad. Sci. U. S. A. 104 (2007) 19464–19469. [118] D. McIlroy, B. Autran, R. Cheynier, S. Wain-Hobson, J.P. Clauvel, et al., Infection frequency of dendritic cells and CD4+ T lymphocytes in spleens of human immunodeficiency virus-positive patients, J. Virol. 69 (1995) 4737–4745. [119] S. Venzke, O.T. Keppler, Role of macrophages in HIV infection and persistence, Expert Rev. Clin. Immunol. 2 (2006) 613–626. [120] L. Wu, V.N. KewalRamani, Dendritic-cell interactions with HIV: infection and viral dissemination, Nat. Rev. Immunol. 6 (2006) 859–868. [121] L. Wu, Biology of HIV mucosal transmission, Curr. Opin. HIV AIDS 3 (2008) 534–540. [122] C.M. Coleman, C.S. Gelais, L. Wu, Cellular and viral mechanisms of HIV-1 transmission mediated by dendritic cells, Adv. Exp. Med. Biol. 762 (2013) 109–130. [123] R. Shen, J.C. Kappes, L.E. Smythies, H.E. Richter, L. Novak, et al., Vaginal myeloid dendritic cells transmit founder HIV-1, J. Virol. 88 (2014) 7683–7688. [124] J.M. Brenchley, T.W. Schacker, L.E. Ruff, D.A. Price, J.H. Taylor, et al., CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract, J. Exp. Med. 200 (2004) 749–759. [125] H.J. Yu, M.A. Reuter, D. McDonald, HIV traffics through a specialized, surfaceaccessible intracellular compartment during trans-infection of T cells by mature dendritic cells, PLoS Pathog. 4 (2008) e1000134. [126] D.A. Kulpa, J.H. Brehm, R. Fromentin, A. Cooper, C. Cooper, et al., The immunological synapse: the gateway to the HIV reservoir, Immunol. Rev. 254 (2013) 305–325. [127] C. Dong, A.M. Janas, J.H. Wang, W.J. Olson, L. Wu, Characterization of human immunodeficiency virus type 1 replication in immature and mature dendritic cells reveals dissociable cis- and trans-infection, J. Virol. 81 (2007) 11352–11362. [128] J. Brenchley, D. Douek, HIV infection and the gastrointestinal immune system, Mucosal Immunol. 1 (2008) 23–30. [129] A. Nazli, O. Chan, W.N. Dobson-Belaire, M. Ouellet, M.J. Tremblay, et al., Exposure to HIV-1 directly impairs mucosal epithelial barrier integrity allowing microbial translocation, PLoS Pathog. 6 (2010) e1000852. [130] J.M. Brenchley, D.A. Price, T.W. Schacker, T.E. Asher, G. Silvestri, et al., Microbial translocation is a cause of systemic immune activation in chronic HIV infection, Nat. Med. 12 (2006) 1365–1371. [131] S.E. Macatonia, N.A. Hosken, M. Litton, P. Vieira, C.S. Hsieh, et al., Dendritic cells produce IL-12 and direct the development of Th1 cells from naive CD4+ T cells, J. Immunol. 154 (1995) 5071–5079. [132] M. Cella, D. Scheidegger, K. Palmer-Lehmann, P. Lane, A. Lanzavecchia, et al., Ligation of CD40 on dendritic cells triggers production of high levels of interleukin-12 and enhances T cell stimulatory capacity: T–T help via APC activation, J. Exp. Med. 184 (1996) 747–752. [133] E. Miller, N. Bhardwaj, Dendritic cell dysregulation during HIV-1 infection, Immunol. Rev. 254 (2013) 170–189. [134] S. Buisson, A. Benlahrech, B. Gazzard, F. Gotch, P. Kelleher, et al., Monocytederived dendritic cells from HIV type 1-infected individuals show reduced ability to stimulate T cells and have altered production of interleukin (IL)-12 and IL-10, J. Infect. Dis. 199 (2009) 1862–1871. [135] N. Derby, E. Martinelli, M. Robbiani, Myeloid dendritic cells in HIV-1 infection, Curr. Opin. HIV AIDS 6 (2011) 379–384. [136] A. Landi, V. Iannucci, A.V. Nuffel, P. Meuwissen, B. Verhasselt, One protein to rule them all: modulation of cell surface receptors and molecules by HIV Nef, Curr. HIV Res. 9 (2011) 496–504.

Please cite this article in press as: M.A.Y. Alqudah, et al., HIV-1 strategies to overcome the immune system by evading and invading innate immune system, HIV & AIDS Review (2015), http://dx.doi.org/10.1016/j.hivar.2015.07.004

G Model

HIVAR-131; No. of Pages 12 M.A.Y. Alqudah et al. / HIV & AIDS Review xxx (2015) xxx–xxx [137] X. Wang, Z. Zhang, S. Zhang, J. Fu, J. Yao, et al., B7-H1 up-regulation impairs myeloid DC and correlates with disease progression in chronic HIV-1 infection, Eur. J. Immunol. 38 (2008) 3226–3236. [138] H.C. Probst, K. McCoy, T. Okazaki, T. Honjo, Broek Mvd, Resting dendritic cells induce peripheral CD8+ T cell tolerance through PD-1 and CTLA-4, Nat. Immunol. 6 (2005) 280–286. [139] K.F. Che, R.L. Sabado, E.M. Shankar, V. Tjomsland, D. Messmer, et al., HIV-1 impairs in vitro priming of naı¨ve T cells and gives rise to contact-dependent suppressor T cells, Eur. J. Immunol. 40 (2010) 2248–2258. [140] M.D. Krathwohla, T.W. Schacker, J.L. Anderson, Abnormal presence of semimature dendritic cells that induce regulatory T cells in HIV-infected subjects, J. Infect. Dis. 193 (2006) 494–504. [141] B. Malleret, B. Maneglier, I. Karlsson, P. Lebon, M. Nascimbeni, et al., Primary infection with simian immunodeficiency virus: plasmacytoid dendritic cell homing to lymph nodes, type I interferon, and immune suppression, Blood 112 (2008) 4598–4608. [142] L. Weiss, V. Donkova-Petrini, L. Caccavelli, M. Balbo, C. Carbonneil, et al., Human immunodeficiency virus-driven expansion of CD4+CD25+ regulatory T cells, which suppress HIV-specific CD4 T-cell responses in HIV-infected patients, Blood 104 (2004) 3249–3256. [143] Z.I. Akhmedjanova, M.V. Zalyalieva, R.R. Begisheva, Influence of histamine on the immunoregulation of HIV-infected patients, IJCRIMPH 4 (2012) 1084–1091. [144] R.R. Zhai, A.P. Jiang, H.B. Wang, L. Ma, X.X. Ren, et al., Histamine enhances HIV-1induced modulation of dendritic cells to skew naive T cell differentiation toward regulatory T cells, Virology 442 (2013) 163–172. [145] J.C. Learmont, A.F. Geczy, J. Mills, L.J. Ashton, C.H. Raynes-Greenow, et al., Immunologic and virologic status after 14 to 18 years of infection with an attenuated strain of HIV-1. A report from the Sydney Blood Bank Cohort, N. Engl. J. Med. 340 (1999) 1715–1722. [146] G.E. Gray, Z. Moodie, B. Metch, P.B. Gilbert, L.G. Bekker, et al., Recombinant adenovirus type 5 HIV gag/pol/nef vaccine in South Africa: unblinded, long-term follow-up of the phase 2b HVTN 503/Phambili study, Lancet Infect. Dis. 14 (2014) 388–396. [147] F.P. Siegal, N. Kadowaki, M. Shodell, P.A. Fitzgerald-Bocarsly, K. Shah, et al., The nature of the principal type 1 interferon-producing cells in human blood, Science 284 (1999) 1835–1837. [148] M.C. Rissoan, V. Soumelis, N. Kadowaki, G. Grouard, F. Briere, et al., Reciprocal control of T helper cell and dendritic cell differentiation, Science 283 (1999) 1183–1186. [149] M. O’Brien, O. Manches, N. Bhardwaj, Plasmacytoid dendritic cells in HIV infection, Adv. Exp. Med. Biol. 762 (2013) 71–107. [150] M. Colonna, G. Trinchieri, Y.-J. Liu, Plasmacytoid dendritic cells in immunity, Nat. Immunol. 5 (2004) 1219–1226. [151] Y.J. Liu, IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors, Annu. Rev. Immunol. 23 (2005) 275–306. [152] G. Sen, R. Ransohoff, Interferon-induced antiviral actions and their regulation, Adv. Virus Res. 42 (1993) 57–102. [153] N. Kadowaki, S. Antonenko, J. Lau, Y. Liu, Natural interferon alpha/beta-producing cells link innate and adaptive immunity, J. Exp. Med. 192 (2000) 219–226. [154] C. Goujon, M.H. Malim, Characterization of the alpha interferon-induced postentry block to HIV-1 infection in primary human macrophages and T cells, J. Virol. 84 (2010) 9254–9266. [155] C. Goujon, T. Schaller, R.P. Galao, S.M. Amie, B. Kim, et al., Evidence for IFN alphainduced SAMHD1-independent inhibitors of early HIV-1 infection, Retrovirology 10 (2013) 23. [156] J.W. Schoggins, S.J. Wilson, M. Panis, M.Y. Murphy, C.T. Jones, et al., A diverse range of gene products are effectors of the type I interferon antiviral response, Nature 472 (2011) 481–485. [157] G. Stary, I. Klein, S. Kohlhofer, F. Koszik, T. Scherzer, et al., Plasmacytoid dendritic cells express TRAIL and induce CD4+ T-cell apoptosis in HIV-1 viremic patients, Blood 114 (2009) 3854–3863. [158] V. Sivaraman, L. Zhang, L. Su, Type I. interferon contributes to CD4+ T cell depletion induced by infection with HIV-1 in the human thymus, J. Virol. 85 (2011) 9243–9250. [159] J.J. Chang, M. Woods, R.J. Lindsay, E.H. Doyle, M. Griesbeck, et al., Higher expression of several interferon-stimulated genes in HIV-1-infected females after adjusting for the level of viral replication, J. Infect. Dis. 208 (2013) 830–838. [160] O. Manches, D. Munn, A. Fallahi, J. Lifson, L. Chaperot, et al., Plasmacytoid DCs induce Tregs through an indoleamine 2,3-dioxygenase-dependent mechanism, J. Clin. Investig. 118 (2008) 3431–3439. [161] L. Cha, C.M. Berry, D. Nolan, A. Castley, S. Fernandez, et al., Interferon-alpha, immune activation and immune dysfunction in treated HIV infection, Clin. Transl. Immunol. 3 (2014) e10. [162] H. Donaghy, B. Gazzard, F. Gotch, S. Patterson, Dysfunction and infection of freshly isolated blood myeloid and plasmacytoid dendritic cells in patients infected with HIV-1, Blood 101 (2003) 4505–4511. [163] H. Donaghy, A. Pozniak, B. Gazzard, N. Qazi, J. Gilmour, et al., Loss of blood CD11c(+) myeloid and CD11c( ) plasmacytoid dendritic cells in patients with HIV-1 infection correlates with HIV-1 RNA virus load, Blood 98 (2001) 2574–2576. [164] J. Pacanowski, S. Kahi, M. Baillet, P. Lebon, C. Deveau, et al., Reduced blood CD123+ (lymphoid) and CD11c+ (myeloid) dendritic cell numbers in primary HIV-1 infection, Blood 98 (2001) 3016–3021. [165] E.R. Wonderlich, S.M. Barratt-Boyes, A dendrite in every pie: myeloid dendritic cells in HIV and SIV infection, Virulence 3 (2012) 647–653.

11

[166] P. Fitzgerald-Bocarsly, E.S. Jacobs, Plasmacytoid dendritic cells in HIV infection: striking a delicate balance, J. Leukoc. Biol. 87 (2010) 609–620. [167] C. Lehmann, M. Lafferty, A. Garzino-Demo, N. Jung, P. Hartmann, et al., Plasmacytoid dendritic cells accumulate and secrete interferon alpha in lymph nodes of HIV-1patients, PLoS ONE 5 (2010) e11110. [168] S.M. Dillon, K.B. Robertson, S.C. Pan, S. Mawhinney, A.L. Meditz, et al., Plasmacytoid and myeloid dendritic cells with a partial activation phenotype accumulate in lymphoid tissue during asymptomatic chronic HIV-1 infection, J. Acquir. Immune Defic. Syndr. 48 (2008) 1–12. [169] A. Biancotto, J.C. Grivel, S.J. Iglehart, C. Vanpouille, A. Lisco, et al., Abnormal activation and cytokine spectra in lymph nodes of people chronically infected with HIV-1, Blood 109 (2007) 4272–4279. [170] R. Badolato, C. Ghidini, F. Facchetti, F. Serana, A. Sottini, et al., Type I interferondependent gene MxA in perinatal HIV-infected patients under antiretroviral therapy as marker for therapy failure and blood plasmacytoid dendritic cells depletion, J. Transl. Med. 6 (2008) 9. [171] C.C. Carter, A. Onafuwa-Nuga, L.A. McNamara, J.t. Riddell, D. Bixby, et al., HIV-1 infects multipotent progenitor cells causing cell death and establishing latent cellular reservoirs, Nat. Med. 16 (2010) 446–451. [172] A. Alexaki, B. Wigdahl, HIV-1 infection of bone marrow hematopoietic progenitor cells and their role in trafficking and viral dissemination, PLoS Pathog. 4 (2008) e1000215. [173] V. Bordoni, M. Bibas, D. Viola, A. Sacchi, C. Agrati, et al., Chronic HIV-infected patients show an impaired dendritic cells differentiation of bone marrow CD34+ cell, J. Acquir. Immune Defic. Syndr. 64 (2013) 342–344. [174] V. Bordoni, M. Bibas, D. Viola, A. Sacchi, C. Agrati, et al., HIV impairs CD34+derived monocytic precursor differentiation into functional dendritic cells, J. Acquir. Immune Defic. Syndr. 64 (2013) 342–344. [175] Y. Guo, W.W. Xu, J. Song, W. Deng, D.Q. Liu, et al., Intracellular overexpression of HIV-1 Nef impairs differentiation and maturation of monocytic precursors towards dendritic cells, PLoS ONE 7 (2012) e40179. [176] Y. Arinobu, H. Iwasaki, K. Akashi, Origin of Basophils and Mast Cells, Allergol. Int. 58 (2009) 21–28. [177] K. Oh, T. Shen, G. Le Gros, B. Min, Induction of Th2 type immunity in a mouse system reveals a novel immunoregulatory role of basophils, Blood 109 (2007) 2921–2927. [178] E. Schneider, N. Thieblemont, M.L. De Moraes, M. Dy, Basophils: new players in the cytokine network, Eur. Cytokine Netw. 21 (2010) 142–153. [179] S.J. Galli, Mast cells and basophils, Curr. Opin. Hematol. 7 (2000) 32–39. [180] S. Galli, New concepts about the mast cell, N. Engl. J. Med. 328 (1993) 257–265. [181] J.T. Schroeder, Basophils beyond effector cells of allergic inflammation, Adv. Immunol. 101 (2009) 123–161. [182] D. Metcalfe, D. Baram, Y. Mekori, Mast cells, Physiol. Rev. 77 (1997) 1033–1079. [183] M. Clerici, F.T. Hakim, D.J. Venzon, S. Blatt, C.W. Hendrix, et al., Changes in interleukin-2 and interleukin-4 production in asymptomatic, human immunodeficiency virus-seropositive individuals, J. Clin. Investig. 91 (1993) 759–765. [184] M. Clerici, G. Shearer, A Th1–Th2 switch is a critical step in the etiology of HIV infection, Immunol. Today 14 (1993) 107–111. [185] E. Maggi, M. Mazzetti, A. Ravina, F. Annunziato, M. de Carli, et al., Ability of HIV to promote a TH1 to TH0 shift and to replicate preferentially in TH2 and TH0 cells, Science 265 (1994) 244–248. [186] G. Marone, G. Florio, M. Triggiani, A. Petraroli, A. de Paulis, Mechanisms of IgE elevation in HIV-1 infection, Crit. Rev. Immunol. 20 (2000) 477–496. [187] J. Hanzlikova, D. Sedlacek, M. Liska, J. Gorcikova, T. Vlas, et al., Histamine increases the level of IFNg produced by HIV-1 specific CTLs and this production depends on total IgE level, J. Immunol. Methods 375 (2012) 1–6. [188] T. Yoshimoto, Basophils as T(h)2-inducing antigen-presenting cells, Int. Immunol. 22 (2010) 543–550. [189] V. Patella, G. Florio, A. Petraroli, G. Marone, HIV-1 gp120 induces IL-4 and IL-13 release from human Fc epsilon RI+ cells through interaction with the VH3 region of IgE, J. Immunol. 164 (2000) 589–595. [190] A.d. Paulis, G. Florio, N. Prevete, M. Triggiani, I. Fiorentino, et al., HIV-1 envelope gp41 peptides promote migration of human Fc epsilon RI+ cells and inhibit IL-13 synthesis through interaction with formyl peptide receptors, J. Immunol. 169 (2002) 4559–4567. [191] J.B. Sundstrom, D.M. Little, F. Villinger, J.E. Ellis, A.A. Ansari, Signaling through Toll-like receptors triggers HIV-1 replication in latently infected mast cells, J. Immunol. 172 (2004) 4391–4401. [192] J.B. Sundstrom, J.E. Ellis, G.A. Hair, A.S. Kirshenbaum, D.D. Metcalfe, et al., Human tissue mast cells are an inducible reservoir of persistent HIV infection, Blood 109 (2007) 5293–5300. [193] N. Ngo-Giang-Huong, D. Candotti, A. Goubar, B. Autran, M. Maynart, et al., HIV type 1-specific IgG2 antibodies: markers of helper T cell type 1 response and prognostic marker of long-term nonprogression, AIDS Res. Hum. Retrovir. 17 (2001) 1435–1446. [194] N. Chin’ombe, W.R. Bourn, A.L. Williamson, E.G. Shephard, Oral vaccination with a recombinant Salmonella vaccine vector provokes systemic HIV-1 subtype C Gagspecific CD4+ Th1 and Th2 cell immune responses in mice, Virol. J. 6 (2009) 87. [195] K. Banerjee, P.J. Klasse, R.W. Sanders, F. Pereyra, E. Michael, et al., IgG subclass profiles in infected HIV type 1 controllers and chronic progressors and in uninfected recipients of Env vaccines, AIDS Res. Hum. Retrovir. 26 (2010) 445–458. [196] B. Vingert, D. Benati, O. Lambotte, P. de Truchis, L. Slama, et al., HIV controllers maintain a population of highly efficient Th1 effector cells in contrast to patients treated in the long term, J. Virol. 86 (2012) 10661–10674.

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[197] M.L. Visciano, M. Tagliamonte, M.L. Tornesello, F.M. Buonaguro, L. Buonaguro, Effects of adjuvants on IgG subclasses elicited by virus-like particles, J. Transl. Med. 10 (2012) 4. [198] A.U. Bielinska, K.W. Janczak, J.J. Landers, D.M. Markovitz, D.C. Montefiori, et al., Nasal immunization with a recombinant HIV gp120 and nanoemulsion adjuvant produces Th1 polarized responses and neutralizing antibodies to primary HIV type 1 isolates, AIDS Res. Hum. Retrovir. 24 (2008) 271–281. [199] N.V. Serbina, T. Jia, T.M. Hohl, E.G. Pamer, Monocyte-mediated defense against microbial pathogens, Annu. Rev. Immunol. 26 (2008) 421–452. [200] T. Zhu, D. Muthui, S. Holte, D. Nickle, F. Feng, et al., Evidence for human immunodeficiency virus type 1 replication in vivo in CD14(+) monocytes and its potential role as a source of virus in patients on highly active antiretroviral therapy, J. Virol. 76 (2002) 707–716. [201] V. Arfi, L. Riviere, L. Jarrosson-Wuilleme, C. Goujon, D. Rigal, et al., Characterization of the early steps of infection of primary blood monocytes by human immunodeficiency virus type 1, J. Virol. 82 (2008) 6557–6565. [202] P. Delobel, K. Sandres-Saune, M. Cazabat, F.E. L’Faqihi, C. Aquilina, et al., Persistence of distinct HIV-1 populations in blood monocytes and naive and memory CD4 T cells during prolonged suppressive HAART, AIDS 19 (2005) 1739–1750. [203] S. Crowe, T. Zhu, W.A. Muller, The contribution of monocyte infection and trafficking to viral persistence, and maintenance of the viral reservoir in HIV infection, J. Leukoc. Biol. 74 (2003) 635–641. [204] Y. Persidsky, A. Ghorpade, J. Rasmussen, J. Limoges, X.J. Liu, et al., Microglial and astrocyte chemokines regulate monocyte migration through the blood–brain barrier in human immunodeficiency virus-1 encephalitis, Am. J. Pathol. 155 (1999) 1599–1611. [205] T. Fischer-Smith, S. Croul, A.E. Sverstiuk, C. Capini, D. L’Heureux, et al., CNS invasion by CD14+/CD16+ peripheral blood-derived monocytes in HIV dementia: perivascular accumulation and reservoir of HIV infection, J. Neurovirol. 7 (2001) 528–541. [206] P.D. Smith, G. Meng, J.F. Salazar-Gonzalez, G.M. Shaw, Macrophage HIV-1 infection and the gastrointestinal tract reservoir, J. Leukoc. Biol. 74 (2003) 642–649. [207] M. Jouve, N. Sol-Foulon, S. Watson, O. Schwartz, P. Benaroch, HIV-1 buds and accumulates in ‘‘nonacidic’’ endosomes of macrophages, Cell Host Microbe 2 (2007) 85–95.

[208] F. Groot, S. Welsch, Q.J. Sattentau, Efficient HIV-1 transmission from macrophages to T cells across transient virological synapses, Blood 111 (2008) 4660–4663. [209] I. Kadiu, H.E. Gendelman, Human immunodeficiency virus type 1 endocytic trafficking through macrophage bridging conduits facilitates spread of infection, J. Neuroimmune Pharmacol. 6 (2011) 658–675. [210] Y. Ghiglione, G. Turk, Nef performance in macrophages: the master orchestrator of viral persistence and spread, Curr. HIV Res. 9 (2011) 505–513. [211] G. Herbein, A. Varin, A. Larbi, C. Fortin, U. Mahlknecht, et al., Nef and TNFalpha are coplayers that favor HIV-1 replication in monocytic cells and primary macrophages, Curr. HIV Res. 6 (2008) 117–129. [212] S.L. Lamers, G.B. Fogel, E.J. Singer, M. Salemi, D.J. Nolan, et al., HIV-1 Nef in macrophage-mediated disease pathogenesis, Int. Rev. Immunol. 31 (2012) 432–450. [213] A.E. Cardona, E.P. Pioro, M.E. Sasse, V. Kostenko, S.M. Cardona, et al., Control of microglial neurotoxicity by the fractalkine receptor, Nat. Neurosci. 9 (2006) 917–924. [214] M. Zhang, X. Li, X. Pang, L. Ding, O. Wood, et al., Identification of a potential HIV-induced source of bystander-mediated apoptosis in T cells: upregulation of trail in primary human macrophages by HIV-1 tat, J. Biomed. Sci. 8 (2001) 290–296. [215] S. Bellino, A. Tripiciano, O. Picconi, V. Francavilla, O. Longo, et al., The presence of anti-Tat antibodies in HIV-infected individuals is associated with containment of CD4+ T-cell decay and viral load, and with delay of disease progression: results of a 3-year cohort study, Retrovirology 11 (2014) 9. [216] G. Corro, C.M. Crudeli, C.A. Rocco, S.A. Marino, L. Sen, High levels of anti-Nef antibodies may prevent AIDS disease progression in vertically HIV-1-infected infants, J. Int. AIDS Soc. 17 (2014) 18790. [217] S.H. Naik, P. Sathe, H.Y. Park, D. Metcalf, A.I. Proietto, et al., Development of plasmacytoid and conventional dendritic cell subtypes from single precursor cells derived in vitro and in vivo, Nat. Immunol. 8 (2007) 1217–1226. [218] K. Shortman, S.H. Naik, Steady-state and inflammatory dendritic-cell development, Nat. Rev. Immunol. 7 (2007) 19–30. [219] A. Dzionek, A. Fuchs, P. Schmidt, S. Cremer, M. Zysk, et al., BDCA-2, BDCA-3, and BDCA-4: three markers for distinct subsets of dendritic cells in human peripheral blood, J. Immunol. 165 (2000) 6037–6046.

Please cite this article in press as: M.A.Y. Alqudah, et al., HIV-1 strategies to overcome the immune system by evading and invading innate immune system, HIV & AIDS Review (2015), http://dx.doi.org/10.1016/j.hivar.2015.07.004