Chronic Inflammation in HIV Pathogenesis: Effects on Immune Cells, Organ Systems, and Systemic Consequences

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Chronic Inflammation in HIV Pathogenesis: Effects on Immune Cells, Organ Systems, and Systemic Consequences Dorothy E. Lewis, Jacob P. Couturier Department of Internal Medicine, Division of Infectious Diseases, The University of Texas Health Science Center at Houston, Houston, TX, United States

List of Acronyms and Abbreviations AIDS ALT ART AST CNS CRP CVD FDC GALT HAND HBV HCV HIV-1 IBD I-FABP IFN INSTI IRIS LN LPS LTNP MACS MCP-1

acquired immune deficiency syndrome alanine transaminase antiretroviral therapy aspartate transaminase central nervous system C-reactive protein cardiovascular disease follicular dendritic cells gut-associated lymphoid tissue HIV-associated neurocognitive dementia hepatitis B virus hepatitis C virus human immunodeficiency virus-1 inflammatory bowel disease intestinal fatty acid binding protein interferon integrase strand transfer inhibitor immune reconstitution inflammatory syndrome lymph node lipopolysaccharide long-term nonprogressor multicenter AIDS cohort study monocyte chemoattractant protein-1

Translational Inflammation https://doi.org/10.1016/B978-0-12-813832-8.00006-6

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Copyright © 2019 Elsevier Inc. All rights reserved.

112 MHC MIP-1 NETS NF-κB NK NKT NNRTI N(t)RTI OPG PAMP PD-1 PI RANKL RANTES SIV TCR TIRAP TLR TNFα

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major histocompatibility complex macrophage inflammatory protein neutrophil extracellular traps nuclear factor-kappa-light-chain-enhancer of activated B cells natural killer cells natural killer T cells non-nucleoside reverse transcriptase inhibitor nucleoside/nucleotide reverse transcriptase inhibitor osteoprotegerin pathogen-associated molecular pattern programmed cell death protein 1 protease inhibitor receptor activator of nuclear factor kappa-B ligand regulated on activation, normal T cell expressed and secreted simian immunodeficiency virus T cell receptor toll-interleukin 1 domain-containing adapter protein toll-like receptor tumor necrosis factor alpha

INTRODUCTION TO HIV PATHOGENESIS HIV pathogenesis has three main components: HIV replication characterized by high mutation rates serves to drive and frustrate the immune response trying to contain it; the loss of memory CD4 T cells that fosters opportunistic infections and cancers; and the final key element, broadbased chronic inflammation [1–3]. Early in the HIV epidemic, the notion of inflammation as a factor in pathogenesis was not on the radar because of great concern about the consequences of the loss of CD4 T cells leading to devastating opportunistic infections and cancer. However, there was an observation that suggested that chronic inflammation was a culprit in pathogenesis because of an independent association of numbers of activated CD8 T cells that positively correlated with HIV disease progression [4]. In addition, there was ample evidence of activation-induced apoptosis of both CD4 and CD8 T cells occurring in vivo [5]. This massive activation of T cells in the natural history of HIV infection was so potent that you could draw effector cells right out of an infected person and they killed major histocompatibility complex (MHC)-matched target cells WITHOUT in vitro reactivation [6]. In addition, high levels of B cell activation and development of HIV-specific, but also autoreactive antibodies, were hallmarks of HIV infection [7]. With the onset of highly effective antiretroviral treatment (ART) in 1995, there was a sharp reduction in viral loads in HIV-infected persons to undetectable levels in the blood, along with a reduction in loss of CD4 T cells in most patients and actual recovery of CD4 T cells in many patients [8]. However, chronic inflammation continued and was not fully resolved by ART [9, 10].



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Chronic inflammation was then recognized as a likely separate contributor to HIV pathogenesis. Although many of the factors associated with inflammation normalized after ART, including the levels of CD8 T cell activation and serum neopterin levels, many indicators of inflammation did not return to baseline for reasons that were unclear. In 2006, Brenchley and his colleagues discovered that the likely source of chronic activation during HIV infection was a gut breach [11]. This breach occurs early in infection and is not as severe as in Inflammatory Bowel Disease (IBD), but sufficient to cause increased microbial translocation. In many respects, this breach in HIV resembles gut breaching in obesity, a condition also associated with chronic inflammation [12, 13]. The upregulation of cytokines is not as severe as in Sepsis or in systemic inflammatory response syndrome (SIRS), but sufficient to induce chronic inflammation. Microbial products breach the gut epithelium and the result is continued immune activation even with effective ART. The mechanisms associated with the breach in HIV involves early infection of and loss of critical Th17 cells that sustain elevated activation levels along the gut epithelium [14]. These cells become depleted and do not return after ART treatment, suggesting there is an ongoing mechanism to suppress their return. In addition, there is dysregulation of the Type I interferon (IFN) response, which is believed to contribute to chronic inflammation [15, 16]. Thus, a combination of events serves to instigate chronic inflammation that continues largely unabated, even with effective systemic therapy for HIV infection. A summary of the many impacts of intestinal breaching upon immunity and organ systems is provided in Fig. 6.1 and further discussed later in this chapter.

INFLUENCE OF GUT BREACH ON CHRONIC INFLAMMATION Much is known about how microbes and their products induce inflammation. Bacteria come equipped with toll-like receptor (TLR) ligands, also known as pathogen-associated molecular patterns (PAMPs), which interact with TLR receptors on the surface and within many cell types to induce innate responses in immune cells, including T cells. There are at least nine TLR recognition molecules, TLR1 to TLR9. These pathogen-­ associated molecules interact with ligands either on the surface (TLR2 and TLR4) or inside cells (TLRs 1, 3, and 5–9). They induce activation of cells via two main molecular pathways, MyD88 and Toll-interleukin 1 domain-­ containing adapter protein (TIRAP) [17–20]. The main consequence of this activation is the production of inflammatory cytokines and functional changes depending on the cell type. Gut microbe-induced inflammation is well-known to occur during inflammatory bowel disease and obesity, but was not recognized as a clear

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Tissue damage and organ dysfunction Systemic inflammation

Activated immune cells

Immune perturbances Th17 cells

(Intestinal lumen)

NK cell function

HIV replication

Microbial, TLR ligands

Platelet activation C-reactive protein D-dimer Soluble CD14

Neutrophil function

Soluble CD163

B cell activation, malignancies

LPS

T cell activation, exhaustion, apoptosis

IL-8

NKT cell depletion

IL-18

Monocyte/Macrophage activation, M1 polarization

TNFα

Acute (days-weeks)

Lymph node activation, fibrosis Brain: neuronal degeneration and altered cognition, glial inflammation Abnormal metabolism Cardiovascular disease (CVD) Obesity, Diabetes Kidney dysfunction

IL-6

Liver dysfunction, steatosis

IL-1β

Bone defects, altered densities

MCP-1

Premature aging

Chronic (months-years)

FIG.  6.1  Disruption of microbial and immune homeostasis subsequent to intestinal breaching during HIV infection results in persistent immune activation, chronic inflammation, and tissue pathologies. In HIV-infected persons, damage to intestinal epithelium and microbial translocation is attributable to at least three major components, chronic activation of innate (monocytes/macrophages, and NK and NKT cells) and adaptive (T cells and B cells) immune cells, HIV replication primarily in CD4 T cells, and the release and systemic distribution of microbial ligands. Such events continue for days and weeks during acute infection, of which the severity of inflammation and patient status can be monitored by various techniques such as measurement of plasma viral loads via PCRs for HIV RNA, examination of activation marker expression by circulating immune cells by flow cytometry, or measurement of microbial proteins (mainly LPS) and immunological factors (cytokines, chemokines, and soluble CD14 and CD163) in serum by ELISAs. Despite antiretroviral treatment that effectively suppresses HIV replication, these changes to intestinal and immune functions continue for months to years, typically resulting in more widespread tissue damage and organ dysfunction.

contributor for HIV pathogenesis until approximately 2006 [11]. Chronic inflammation also occurs during obesity and is also associated with microbial translocation and alterations in the gut microbiome [12, 13]. The gut microbiome is further altered during HIV infection, in which normal flora species such as Prevotella bacteria become dominant. However, the microbiome does typically normalize during cART treatment [21]. A key study demonstrating that microbial translocation was an essential factor in systemic inflammation was conducted by Kristoff et al. [22], who showed that blocking microbial translocation in SIV-infected pig-tailed macaques dramatically reduced



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T cell activation and production of inflammatory cytokines, as well as lowered plasma viral loads. The mechanisms associated with intestinal breach also include loss of Th17 cells, a key CD4 T cell subset that normally regulates activation levels and responses to microbes at the gut epithelium. In addition, there are alterations in Type I IFN responses and an accumulation of macrophages during early acute infection in animal models [23–25].

SYSTEMIC INFLAMMATION IN HIV HIV infection is associated with plasma elevations of pro-inflammatory cytokines, notably TNFα and IL-6 [26]. During acute infection, elevated levels of cytokines associated with fever are observed, such as IL-1β. Many studies have described the inflammation during untreated HIV infection as a cytokine storm, although not as severe as what occurs in sepsis, but with similar elevated cytokines. Other serum markers associated with increased cardiovascular disease, including elevated C-reactive protein (CRP) and the coagulation factor, D-dimer, have also been observed during HIV infection [27]. There is also evidence of two-fold to three-fold higher levels of IL-1β, IL-17, and IL-6 in ART-treated patients with blood CD4 T counts under 200/mm3, indicating that chronic immune activation and CD4 T cell recovery post-ART might be linked [28]. Increased T cell activation levels were associated with higher plasma levels of soluble CD14, TNFα, IL-6, IL-15, IL-18, soluble CD163, and IL-12p70, indicating that an inflammatory myeloid state remains in ART-treated patients.

IMPACT ON ADAPTIVE IMMUNITY Effects on T cells Both CD4 and CD8 T cells exhibit indicators for chronic inflammation as measured by increased activation markers and increased cell death in untreated infection. A key early marker of chronic activation was elevation of CD38 expression by CD8 T cells which independently predicted HIV disease progression [4]. In treated HIV infection, the levels of CD38 are reduced, but still remain above normal [29]. CD38 is a surface ectoenzyme that is a cyclic ADP-ribose hydrolase involved in calcium ion regulation and likely reflects effector function of the T cell. Most detrimental for the host is the impact that high levels of immune activation have on T cell recovery post-ART. In patients whose CD4 recovery was reduced post-ART, there was increased levels of both CD4+ and CD8+ T cells expressing higher CD38 HLA.DR, as well as more T cells expressing the “immune exhaustion” marker, PD-1 [29]. This suggests that chronic immune

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­activation in some way impairs the rebound of CD4 T cells. Whether persistent low-level HIV replication is a driver of increased T cell activation during ART is unclear, as some studies show association of HIV DNA and RNA levels with T cell activation levels [30], whereas more recent studies show no significant correlations [31]. The levels of CD38 do not normalize on either CD4 or CD8 T cells post-ART [32]. There is also more T cell apoptosis which continues despite ART treatment [33, 34]. HIV infection is characterized by greater T cell activation with more Th1-like cells and fewer T regulatory cells (Tregs), both of which tend to normalize postART [35]. CD8 T cells have reduced functions because of increased PD-1 expression, although such expression may enhance their survival [36]. Resolution of Th17 loss in the gut does not take place post-ART which allows for continued higher levels of T cell activation and apoptosis, as well as altered or reduced functionality in those T cells that remain [36, 37].

Effects on B cells Hyper-gammaglobulinemia is a hallmark of HIV infection along with polyclonal B cell activation. The composition of peripheral blood B cells in HIV patients is also different in which some populations that normally reside in the bone marrow, including immature B cells and plasmablasts, begin to circulate in blood [38]. B cell activation continues post-ART and is associated with more B cell malignancies including Burkitt’s lymphoma, Diffuse large B-cell lymphoma, and non-Hodgkin’s lymphomas [39]. Several mechanisms might be responsible for the increased B cell activation, including the gut breach. There is increased p38 phosphorylation in B cells of HIV patients, indicative of TLR2-induced activation and suggests a direct effect of microbial translocation on B cell function [40, 41]. However, there are also indirect mechanisms related to higher levels of pro-inflammatory cytokines including TNFα and Il-6 that serve to drive B cell differentiation. Many of these profound abnormalities are reduced by ART; however, the deficiency in numbers and responsiveness of memory B cells persists and may be driven by the continued microbial translocation. This deficiency likely influences the poor response to vaccines such as Influenza vaccine in HIV-infected cohorts [42].

IMPACT ON INNATE IMMUNITY Natural Killer Cells Natural killer cells (NK) respond to the threat of HIV by increasing production of chemokines, such as RANTES (CCL5) and macrophage inflammatory proteins (MIP-1α or MIP-1β) which serve to impede infections by CCR5-utilizing HIV strains [43]. The distribution of peripheral NK cells is,



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however, altered such that there are reduced numbers of CD56-dim NK cells and more CD56-bright cells, indicating reduced cytotoxic function. In viremic HIV patients, the major activating NK receptors are downregulated, but these receptors normalize after ART. The function of NK cells in viremic patients is reduced, and there is some recovery post-ART, although not to normal levels. Recent evidence suggests that the levels of chronic immune activation that continue in patients who do not recover CD4 T cells post-ART were reflected by elevated expression of activation markers on the CD56dim subset of NK cells. These cells actually mediated cytotoxicity against self CD4 T cells, suggesting a possible mechanism for lack of CD4 recovery [44].

Natural Killer T cells Natural killer T cells (NKT) are cells that express a semiinvariant T cell receptor (TCR) with a constant alpha chain and an array of beta chains that preferentially recognize lipid antigens via CD1d presentation. There are two types of NKT cells: Type I which are restricted in TCR diversity, and Type II with a more diverse TCR repertoire. These cells are important for controlling viral infections and in cancer surveillance [45]. Type I NKT cells are depleted early during infection in both HIV-infected humans and in SIV-infected rhesus macaques, but this depletion is partially reversed by ART [45, 46]. The impact of HIV infection on Type II NKT cells is mostly unknown. Lower NKT cell numbers in the periphery is associated with a higher rate of malignancies during HIV infection [46–48]. Activated CD4 T cell numbers correlate with the degree of loss of these cells, indicating that inflammation might play a role indirectly. However, HIV-infected long-term nonprogressors (LTNP or elite controllers) retain normal levels of NKT cells, indicating these cells play a role in non-ART containment of HIV in vivo [49].

Neutrophils Neutrophils are scavenger cells that act as a first line of defense against pathogenic challenges, especially in the skin and mucosa. Neutrophil function is especially important for phagocytosis of microorganisms at the site of infection and is important in host innate immune activation. Neutrophils respond to HIV by production of alpha defensins and neutrophil extracellular traps (NETS) which can inactivate HIV in vitro [50]. Circulating neutrophils in HIV patients also express more PD-1, believed to be induced by TLR7/8 ligands, lipopolysaccharide (LPS), or IFNα. In addition, HIV infection can also induce PD-1 expression on neutrophils. These neutrophils suppress T cell function ex vivo which may also occur in vivo. Studies suggest that continual microbial translocation affects neutrophil function and consequently suppresses T cell function in vivo [51, 52].

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Monocytes and Macrophages Early in the AIDS epidemic, it was recognized that circulating blood monocytes and tissue macrophages of HIV-infected patients were unusually activated and their functions altered [53–55]. These cells are targets for HIV in vivo but do not die as readily as T cells, and further serve as additional persistent reservoirs for HIV during suppressive ART. A hallmark feature of macrophage activation contributing to systemic inflammation during HIV infection is increased production of pro-inflammatory cytokines and chemokines including IL-6, TNFα, and Macrophage Inflammatory Protein 1 (MIP-1). Indices of microbial translocation such as plasma LPS are associated with monocyte activation in chronically infected HIV patients. Although monocyte/macrophage activation levels decrease post-ART, they still remain elevated compared to healthy uninfected persons. Their activated state also contributes to cardiovascular disease (CVD), metabolic changes, and neurocognitive decline in HIV patients [56, 57]. Monocytes and macrophages can display highly diverse phenotypes and functions, and studies show that HIV replicates differently in M1 pro-inflammatory and M2 anti-inflammatory macrophage subsets [58, 59]. Although monocyte/macrophage activation is generally associated with systemic inflammation during HIV infection, it is likely that different monocyte and macrophage subsets influence inflammation to varying degrees.

IMPACT OF INFLAMMATION ON ORGAN SYSTEMS AND COMORBIDITIES IN HIV Lymph Nodes The lymph nodes (LN) are a major tissue reservoir and sanctuary for HIV-infected CD4 T cells. Untreated HIV infection is associated with germinal center expansion and trapping of HIV particles by antibodies in the follicular dendritic cell (FDC) region of lymph nodes [60]. Eventually, lymph nodes become acellular and fibrotic and the architecture is destroyed. In ART-treated patients, recent data suggests that there is increased inflammation and CD4 T cell activation in the lymph nodes, and those on therapy who are unable to control HIV exhibit the highest activation levels and viral loads [61]. There is also modest arterial inflammation associated with lymph nodes that is correlated with C-reactive protein and IL-6 levels, as well as activated monocytes [62]. Both HIV-infected humans and SIV-infected monkeys demonstrate marked hyperplasia, with high levels of B cells and a typical infiltration of CD8 T cells into germinal centers, LN regions which normally do not harbor many CD8 T cells [63, 64]. There are also increased macrophages, granulocytes, and Tregs in the T cell zones, suggestive of the immune system trying to contain the



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massive activation occurring in the lymph nodes. Such devastating effects on lymph node architecture and function are reduced by ART but do not recover entirely [3]. Recovery of lymphocytic cellularity depends on the levels of fibrosis in each lymph node and the ability of migrating naïve lymphocytes to repopulate, so such recovery is variable for each lymph node in a person and between people.

Liver Most effects regarding HIV and liver morbidity happen because of coinfection with Hepatitis B or C viruses (HBV or HCV). In these settings, the pathogenesis of liver disease in coinfected people typically progresses more rapidly with higher cases of liver-related mortality. Increased hepatic damage is associated with elevated aspartate transaminase (AST), alanine transamin‑ase (ALT), and serum LPS. Serum levels of intestinal fatty acid-binding protein (I-FABP) are similarly increased in both coinfected and HIV mono-infected persons [65]. However, there is evidence that HIV mono-infection in the setting of ART treatment can also lead to liver disease in conjunction with high HIV viral loads, prolonged drug treatment, alcohol abuse, and advanced age. Such pathogenesis is likely associated with chronic inflammatory conditions and responses to TLRs from the gut breach [66]. The liver also harbors abundant HIV-infected immune cells during ART treatment, and hepatocytes themselves might be infected, which may further exacerbate inflammatory pathways [67].

Kidney HIV-infected individuals receiving ART are at risk for chronic kidney disease and nephropathy, and this pathogenesis has an inflammatory component [68]. In the Multicenter AIDS Cohort Study (MACS) of HIVinfected men, higher creatinine clearance ratios and increased glomerular filtration rates were observed and associated with increased inflammatory markers including plasma TNF receptor 2 (TNFR2), CD25 receptor, CD27, gp130, and soluble CD14. Similar to the liver, HIV-infected immune cells, or infected epithelial cells, can persist in the kidney and possibly contribute to inflammation and tissue pathologies. Kidney disease is also likely associated with higher levels of cardiovascular disease in HIV patients.

Adipose Tissue Adipose tissue is associated with systemic inflammation and also likely related to HIV pathogenesis because most HIV patients experience metabolic dysfunction [69]. Adipose tissue is categorized into subcutaneous (underlying skin) and visceral (surrounding internal organs) fat depots, and

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extensively associated with tissues and organs that harbor HIV-infected immune cells such as lymph nodes (perinodal), intestines (mesenteric), heart (epicardial), and bone marrow (MAT). There is an accumulation of activated pro-inflammatory immune cells in adipose tissue, including CD8 and CD4 T cells, NK and NKT cells, macrophages, and granulocytes [70]. The long-term elevated production of pro-inflammatory mediators such as IL-6, IL-8, TNFα, and monocyte chemoattractant protein (MCP-1) by ­adipocytes and adipose-resident immune cells exacerbates adipose inflammation. The infiltration of TLR ligands such as LPS into visceral fat depots may further contribute to adipose inflammation during obesity and HIV infection [12, 71]. Studies also suggest that many HIV patients are at higher risk for obesity and that high-fat diet can worsen inflammation and disease progression [72, 73]. An alarming observation late in the era of ART is that lean HIV patients on effective ART continue to experience a number of chronic inflammatory conditions and immune activation, which in many ways resemble those of overweight or obese uninfected persons as summarized in Fig. 6.2. Recent studies show that subcutaneous and visceral fat depots harbor HIV-infected CD4 T cells and macrophages in humans and rhesus monkeys [74–76]. T cells and macrophages in adipose tissue of HIV-infected humans or SIV-infected monkeys exhibit pro-inflammatory phenotypes and functions, such as differentiation into Th1 or Th17 CD4 T cells or M1 macrophages and production of IL-2, IFNγ, IL-17A, IL-6, and TNFα [74, 75]. These activated immune cells may worsen adipose tissue function and health by impairing adipocyte growth and metabolism, promoting mitochondrial dysfunction, and increasing the production of inflammatory mediators by adipocytes. Additionally, levels of anti-inflammatory Tregs in adipose tissue may decrease during obesity and HIV infection and lose their important role in regulating inflammation [77].

Metabolic Syndrome Early in the HIV epidemic it was noted that some patients experienced significant amounts of wasting and cachexia. Following initiation of ART regimens, the focus of clinical research shifted to lipodystrophy and fat redistribution—wasting in anatomic compartments such as the limbs and face, and accumulation of fat mainly in abdominal and visceral regions [72, 73, 78, 79]. The wasting is believed to be due mainly to treatment with protease inhibitors (PI) and some nucleoside/nucleotide reverse transcriptase inhibitors (N(t)RTI) that are toxic to mitochondria, with some of the drugs causing more toxicity than others. Within approximately two years of ART treatment, there is a shift to weight gain for many people, in addition to altered cholesterol and triglyceride levels. These changes go hand-in-hand with the increased cardiovascular risk in these patients. The



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Inflammatory pathologies common between obesity and HIV chronic infection Intestinal breaching and leakage (increased TLR agonists– LPS) Immunological changes (activated T cells, decreased Tregs, increased M1 macrophages, inflammasome activation) Elevated circulating inflammatory mediators (IL6, IL8, IL1β, IL18, TNFα, sCD14, CRP, LPS)

Obese Uninfected

Metabolic dysfunctions (insulin resistance, diabetes, abnormal adipose tissue function, ectopic fat deposition in liver, muscles, heart, mitochondrial toxicities) Cardiovascular disease

Lean HIVInfected

Fibrosis (liver, lymph nodes) Increased risk for cancers Impaired neurological and cognitive functions Premature aging

FIG. 6.2  The many similarities of chronic inflammation, immune activation, and comorbidities between obese persons and HIV-infected patients. Recent research into obesity, diabetes, and metabolic disorders has revealed startling commonalities that obese uninfected persons share with HIV-infected patients, even in lean states. Notably, immune activation, systemic inflammation, and abnormal metabolic conditions are among the most commons events during obesity and HIV infection. However, it is not yet as clear how much intestinal disruption and microbial dissemination contributes to inflammation and comorbidities during obesity as it is known for HIV infections. One benefit from continued research is that therapeutic strategies targeting intestinal breaching, immune activation, and chronic inflammation during HIV infection are likely to have applications to obesity and vice versa.

continued infection of adipose tissue immune cells might also play a role in metabolic disorder, as a single protein of HIV, Vpr, in mouse models can cause metabolic problems resembling those of HIV patients [80].

Cardiovascular Disease With the onset of ART therapy in 1995, the incidence of cardiovascular disease, coagulopathy, and stroke in HIV patients escalated, in part because patients were living longer. This increased cardiovascular risk was associated with elevations in serum cholesterol and triglycerides, and increased intimal thickness of the carotid arteries [81, 82]. Markers of endothelial cell activation are altered in HIV infection as measured by brachial artery reactivity testing, as well as serum markers such as soluble

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VCAM-1 and pro-inflammatory cytokines. Monocytes and macrophages are involved in CVD pathogenesis and their pathogenic roles during HIV infection are increased with the development of more pro-atherogenic macrophages. Plasma soluble CD14 levels predict all-cause mortality in HIV patients and are associated with CVD. In the MACS cohort study, it was also shown that greater coronary stenosis was associated with higher levels of sCD163 (shed by inflammatory macrophages), sCD14, and CCL2 (MCP-1), all suggesting an activated macrophage population in ART-treated HIV patients that promotes CVD [83]. Additionally, higher levels of IL-6 and D-dimer can indicate a greater risk for fatal CVD. Since these risk factors and conditions are generally similar to those found in uninfected people, they can be therapeutically targeted with conventional ­lipid-lowering and antihypertension medications [84].

Bone Health and Metabolism Bone marrow can harbor HIV since there are memory CD4 T cells and macrophages found there [85]. In addition, both HIV infection and ART treatment are independent risk factors for osteoporosis. In untreated HIV patients, there is preferential loss of total hip and trochanter sites over 48 weeks, which correlates with high serum IL-6 levels [86]. Up to twothirds of HIV patients are likely to become osteopenic over time. Fracture prevalence increases in HIV patients treated with ART two-fold to fourfold higher compared to age-matched controls, and both men and women are similarly affected [87]. Because B cells and T cells are both involved in bone remodeling via production of osteoprotegerin (OPG) and receptor activator of nuclear factor kappa-B ligand (RANKL), there is a profound interaction of osteocytes with immune cells, and these interactions are altered by HIV infection and ART treatments [88, 89]. In an animal model, it was elegantly demonstrated that HIV transgenic rats experienced decreases in OPG and increases in RANKL that led to more bone destruction [90]. The effects of ART on bone metabolism are complex and drug-­specific, but both protease inhibitors and NRTIs are associated with increased bone loss in HIV patients. A possible mechanism may involve the rebound of CD4 T cells following ART treatment, which subsequently alters the immune cell balance in bone marrow. Whether chronic inflammation significantly affects bone loss and integrity is mostly unclear, but bone loss has been associated with elevated IL-6 levels in HIV patients [91].

Central Nervous System and Neurocognition One of the most notable sad consequences of HIV infection is that HIV-infected immune cells, particularly macrophages, migrate into the brain, spread virus to other microglial cells and astrocytes, and impair



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neural cognition in up to 70% of patients [92]. Markers of microbial translocation have been correlated with HIV-associated neurocognitive dementia (HAND). Chronic inflammation in the brain is also found during obesity and aging, with elevated levels of NF-κB activation associated with depletion of gonadotropin-releasing hormone (GnRH). NFκB activation is further associated with loss of adult neural stem cells in the hypothalamus [93]. In addition to HIV infection of microglial cells and macrophages in the brain, these cells broadly experience increased activation levels. If ART is started early in infection, less HIV gets into the brain and this is associated with less inflammation and neuronal damage [94, 95]. However, HIV that persists in central nervous system (CNS) tissues such as the brain replicates and mutates differently from virus in the blood and other tissues, suggesting a unique viral reservoir and levels of viral control. Another challenge associated with HIV in the CNS is the limited penetration of antiviral drugs, mainly due to the bloodbrain barrier. Mechanisms to explain the continued CNS activation and inflammation in the context of ART drugs that do penetrate the brain may involve increased protein turnover and responsiveness to continued microbial translocation. A number of microbial pathogens such as Cryptococcus neoformans, Mycobacterium tuberculosis, and Toxoplasma ­gondii can infect CNS tissues of AIDS patients. However, ART treatment can also result in immune reconstitution inflammatory syndrome (IRIS) as the returning T cells respond to the pathogen. Other HIV-associated risk factors can increase the risk of neurocognitive disorder, including illicit drug use, Hepatitis C infection, cardiovascular disease, and sleep apnea [96].

Accelerated Aging Because of effective ART therapy, HIV patients are living longer; however, many patients past fifty years of age may experience accelerated aging with health complications normally found in much older people. A key factor is the development of higher rates of CVD and metabolic disorders [97]. There is also more cognitive decline and loss of bone density with an increase in cancer rates [98]. Frailty rates increase and are associated with low testosterone levels in males. All of these abnormalities are associated with chronic inflammation and have led to the concept of “inflammaging” during HIV infection [99]. However, other studies have challenged the idea of accelerated aging, and higher rates of inflammation and comorbidities in younger patients during HIV infection [100, 101]. Despite conflicting conclusions, there is a consensus that these conditions occur with significant frequency in chronically infected patients and have important implications for HIV treatments.

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TREATMENT STRATEGIES The complexity and multifactorial etiologies of inflammation and comorbidities during HIV infection make treatment difficult. Studies addressing these long-term complications have resulted in mixed conclusions [2]. A successful therapy has used anti-inflammatory statins to decrease immune cell activation and inflammation. However, such treatment may also increase cardiovascular risk. Short-term administration of IL-7 in conjunction with ART improves intestinal function and T cell homeostasis and reduces systemic inflammatory markers. Anti-IL-6 therapy is also currently being tested to reduce inflammation. Another strategy to reduce gut leakiness and microbial translocation has been to treat with rifaximin and sevelamer, but only modest effects were observed. More recent studies suggest that administering probiotics with ART may improve outcome. In SIV-infected rhesus monkeys, an exciting study demonstrated that blocking the gut-homing migration of α4β7 CD4 T cells (via administration of anti-α4β7 antibodies in conjunction with ART treatment) results in viral suppression for extensive time periods, recovery of intestinal Th17 cells, and reduction of inflammatory markers, indicating improvement of intestinal integrity and function, and further highlighting the important relationship between intestinal homeostasis and systemic inflammation [102, 103]. Such a strategy for HIV patients is currently under clinical testing using vedolizumab, an α4β7 antibody treatment recently FDA-approved for ulcerative colitis and Crohn’s disease. With respect to ART optimization, raltegravir (an integrase inhibitor) intensification has been studied, but resulted in no reduction of viral reservoirs and immune cell activation [104]. Despite the difficulties and uncertainties in treating these conditions, accumulating studies have associated early ART initiation with lower persistent viral loads, reduced inflammation, and improved intestinal function. Thus, the current recommendation is to initiate ART as soon as possible postinfection, regardless of CD4 T cell counts, as opposed to previous recommendations of waiting for CD4 counts to fall below certain levels before administering ART. A number of studies and clinical trials are ongoing to address the inflammation and comorbidities during HIV infection.

CONCLUSIONS This review has documented the myriad effects of chronic inflammation during HIV infection. Most cells and tissues of the immune system are significantly impacted, and many organ systems changed in ­function for extended periods of time despite effective ART. The most ­serious

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e­ ffects are associated with increased development of cardiovascular disease, which have similar risk factors as in uninfected people, and may occur in HIV patients at earlier ages. Such comorbidities are considered by many as a “second wave” of consequences of HIV on the host. Reducing chronic inflammation during HIV infection is the focus of many direct interventions and will further be an important element of “functional cures” currently being investigated—enforcing proviral dormancy as an alternative to unsuccessful viral eradication. It is generally believed that stopping the gut breach and restoring Th17 numbers and functions along the gut epithelium would likely alleviate systemic inflammation and many HIVassociated pathologies.

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Glossary Cytokine storm  The massive levels of cytokines and chemokines, mainly pro-inflammatory, including IL-6, TNFα, and IFNγ, in the circulation typically during acute HIV infection. It is believed that such significant production of these factors is attributable mainly to innate and adaptive immune cells in response to initial HIV infection and substantial replication levels. HIV-associated comorbidities  Refers to diseases and tissue or organ pathologies, usually occurring during chronic phases of HIV infection and AIDS which can include cardiovascular disease, inflammatory conditions, metabolic disorders (obesity, diabetes, or insulin resistance), cancers, fibrosis, liver and kidney diseases, bone defects or frailty, neurocognitive dysfunction, or diseases caused by coinfections with HBV, HCV, or M. tuberculosis. Comorbidities became more common later during the ART era due to the significant extension of patient lifespans and long-term side effects of ART regimens.

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HIV persistence and reservoirs Refers to the permanent residence of HIV in cells and tissues (mainly CD4 T cells, macrophages, and lymphoid tissues) of infected patients, despite antiretroviral treatment that fully suppresses viral replication, and the normal functioning of immune cells. A controversial viewpoint with respect to HIV persistence is whether low-level viral replication occurs during fully suppressive ART, which may consequently contribute to chronic immune activation. Hypergammaglobulinemia  The massive polyclonal activation of B cells that leads to abnormal levels of IgG antibodies in the plasma. Hypergammaglobulinemia is a notable event during HIV infection and is attributable to chronic activation of B cells by T cells, cytokines, or microbial products. Immune exhaustion  The decreased functionality and longevity of immune cells, particularly effector and memory T cells, as a consequence of chronic immune activation and inflammation during HIV infection. Exhaustion and senescence of T cells is typically associated with decreased capacity for cytokine production and increased expression of surface proteins such as PD-1, LAG-3, TIM-3, TIGIT, or CTLA-4 which function to suppress T cell activation. Inflammatory markers  Refers to biomarkers such as proteins, lipids, microbial products, or immune activation markers that are typically increased during HIV infection. Common markers to assess inflammation during HIV infection include serum LPS, soluble CD14, soluble CD163, D-dimer, cytokines and chemokines, and circulating T cell activation markers (CD38, HLA.DR, CD25, CD69, or Ki67). Intestinal/gut breach  The transient increased permeability, or leakiness, of the gut epithelial lining due to enterocyte dysfunction and death and impaired tight junctions that results in microbial translocation. Such intestinal damage may be due to multiple factors such as activated immune cells, secreted factors such as cytokines, or disruption of the normal flora and microbial homeostasis. During HIV infection, prolonged intestinal breaching is associated with the activation of numerous innate and adaptive immune cells in the lamina propria, loss of critical Th17 cells, and reduced Type I IFN responses. Loss of intestinal integrity is considered a major cause of chronic inflammation and immune activation during HIV infection, as well as during other inflammatory conditions such as obesity or inflammatory bowel disease. Metabolic syndrome  A common comorbidity during HIV infection with complex etiology and presenting with multiple metabolic abnormalities, notably lipodystrophies and fat redistribution. Metabolic syndrome is often associated with chronic inflammation and diagnosed if a person presents with obesity, increased triglycerides, decreased HDL cholesterol, and increased blood sugar and blood pressure. Antiretroviral drugs are believed to be a major cause of metabolic syndrome in HIV patients, although other factors such as immune activation or microbial products (soluble HIV proteins, for example) can contribute. Microbial translocation  The abnormal dissemination of microbes or their products from the intestinal lumen and epithelial barrier (due to the breakdown or impaired integrity of the intestinal epithelial cells) to the lamina propria and local lymph nodes, and subsequent activation of immune cells. Assessment of microbial translocation can be determined by measurement of serum LPS, LPS-binding protein (LBP), or soluble CD14, and these markers typically correlate with markers of immune activation such as CD38 and HLA. DR expression by circulating T cells. TLR ligands/agonists  Microbial (bacterial, fungal, or viral) extracellular or intracellular proteins, peptides, or nucleic acids that bind to and activate toll-like receptors (TLRs 1–9). Notable examples for HIV-associated inflammation include extracellular LPS, flagellin, and intracellular microbial DNA or RNA.