SIV Infection

C H A P T E R

42 Mucosal Vaccines Against HIV/SIV Infection Hiroyuki Yamamoto1, Hiroshi Ishii1 and Tetsuro Matano1,2 1

AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan 2The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

I. INTRODUCTION This chapter describes the current progress of studies for the development of mucosal HIV vaccines that will induce effective antibody and T cell responses. In the final part of the chapter, we discuss the possible synergistic efficacy of antibody and T cell responses against HIV infection.

II. MUCOSAL VACCINES INDUCING HIV-SPECIFIC ANTIBODY RESPONSES A. Characterization of Anti-HIV Neutralizing Antibodies to Design a Mucosal HIV Vaccine It is now widely recognized that HIV is highly resistant to neutralizing antibodies (NAbs), and it appears practically difficult to design a NAb-inducing vaccine by conventional strategies [1]. Due to the heavy glycosylation of the target envelope (Env) protein [2] and

Mucosal Vaccines DOI: https://doi.org/10.1016/B978-0-12-811924-2.00042-0

its intrinsic morphology [3], the conserved antigenic sites of HIV Env are very difficult for normal anti-Env Abs to access. Anti-HIV NAbs often require to highly mutate by undergoing extensive B cell receptor (BCR) affinity maturation, often to build looped protrusions, mainly composed of complementarity-determining region 3 (CDR3) of the immunoglobulin G (IgG) heavy chain, to reach functionally conserved and cryptic Env epitopes such as the CD4-binding site or other regions [4]. Among such anti-HIV NAbs, a broadly neutralizing HIV antibody (bNAb) against a panel of HIV strains is considered to be the key component to be induced. Recent technical advances in single B cell/antibody isolation [5] have resulted in the identification and characterization of a vast set of bNAbs targeting several critical regions of HIV Env [6]. The important question of an antibody/NAbbased vaccine is where, anatomically, to induce these antibody titers. The two major compartments where these Abs are needed to segregate include the systemic compartment (peripheral

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blood) and mucosal compartment. Considerable interest has been taken in developing a mucosal antibody-based HIV vaccine, owing to the sexually transmitted nature of the virus [7]. In the past three decades, attempts have been made through passive immunization studies, characterization of potent monoclonal anti-HIV bNAbs, and analysis of clinical trials. Extended from these, current studies also aim for highresolution in situ analysis of infected mucosal tissues.

B. Passive Anti-HIV Antibody Administration as a Model of Mucosal Vaccines Because it is immensely difficult to build even a prototype regimen of an antibody-based HIV vaccine, efforts have been made to define the potency of anti-HIV antibodies by passive immunization studies in animal models. To this end, several important factors need to be focused to aim for a mucosal vaccine. First, assessment of antibody-mediated virus protection inevitably requires a sufficient level of viral detection sensitivity after virus challenge, which was achieved in the late 1990s by the establishment of plasma viral RNA quantitation for routine monitoring of in vivo viral replication [8]. Following this step, it was first demonstrated that administration of high-dose HIV-specific polyclonal and monoclonal NAbs can provide sufficient protection against intravenous challenge of chimeric CXCR4-tropic SHIVs (simian-human immunodeficiency viruses) in macaques [9]. The second important aspect is the virus challenge route. Modifying the challenge route of the virus to a mucosal one (e.g., oral, intrarectal, or intravaginal challenge) in macaque passive immunization models has set grounds for adequate estimation of mucosal titers required for the SHIV/SIV protection. A body of work has characterized the efficacy of passively administered anti-HIV polyclonal NAbs

and bNAbs in these mucosal CCR5-tropic SHIV challenge models, and it was found that protection against mucosally challenged virus may not require titers as high as those required against intravenous challenge, providing optimism for development of a mucosal vaccine [10 13]. Another factor related to this is the specificity of the antibody. A recent study has discovered that the biological half-life of bNAbs passively infused by a single administration determines the longevity of sterile protection against repeated intrarectal low-dose SHIV challenges [14]. These results together suggest the importance of attaining sufficient NAb titers at the mucosal interface of infection.

C. Antibody-Related Correlates in HIV Vaccine Clinical Trials Antibodies are composed of five subtypes: IgM, IgG, IgA, IgE, and IgD. IgG is the most predominant effector of systemic Ab titers, whereas IgA dimerizes and often provides bivalent protection on mucosal surfaces. In typical acute viral infections such as influenza virus infection, antiviral IgA antibodies can be the major mucosal effectors for viral blockade [15]. Therefore, it would be straightforward to expect that protective correlates in Ab-based HIV vaccine trials may derive certain protective IgA-related factors by immune correlates analysis. Uniquely differing from this expectation, the RV144 trial in Thailand of a poxvirus vector prime-protein boost vaccination eliciting HIV V1/V2-specific Ab responses as protection correlates [16] showed that a skewing to virus-specific IgG responses was protective, whereas skewing to IgA responses correlated more negatively with protection [17]. One functional in vitro study on these two subtypes later showed that binding of anti-Env IgA impedes the binding of anti-Env IgG, and the resulting cellular immunemediated effector function, providing a potential explanation of their discordant correlations [18]. These results collectively indicate that mucosal

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Ab-based HIV vaccines may need to employ mechanisms distinct from conventional vaccines to afford protection. Among these, an important candidate to focus on is the Ab Fc (constant region)-mediated effector function. In one of the passive immunization studies, abrogation of Fc receptor binding in bNAb b12 resulted in impairment of sterile SHIV protection, which provided a rationale for taking Fc effector functions into consideration [19]. Furthermore, a genotype subgroup analysis on the RV144 trial has found that the rate of protection afforded differed strikingly when participants were classified by their Fc gamma receptor polymorphisms [20], which further implicated the potential involvement of Ab effector functions in this trial. A meta-analysis performed in another study found that Fc-receptor-related profiles of anti-HIV antibodies, such as subclasses, differed among vaccine trials, which could also withhold unknown links with the outcomes [21]. Collectively, clinical trials have indicated that Ab-related protective correlates may indeed exist in an HIV vaccine, posing fundamental questions for the precise mechanism of protection against mucosal HIV transmission.

D. Analysis of Mucosal Tissues and Ab Effector Function for Vaccine Design To develop a robust Ab-based mucosal HIV vaccine, it is critical to technically enrich analysis of the mucosal site of infection. The most important step here is in situ visualization of SHIV/SIV infection in the mucosa. One practical approach for establishing such models is the use of female nonhuman primates that have been vaginally challenged with SIV or SHIV. Here, the goal is to characterize viral dynamics and infection against the very first encountered target cells, requiring sophisticated techniques for probing. Visualization of SIV infection on cells in the female reproductive tract has precisely mapped the distribution of infected cells in the mucosa, providing morphological clues to attain protective HIV Ab titers [22]. In handling mucosal

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tissues for such analysis, it is important to take into account the influence of the menstrual cycle and related mucosal changes. Studies have addressed this by monitoring the change of virus target interactions by topical administration of progestins in SIV-infected female rhesus macaques [23]. Furthermore, recent tissue culture analysis of male penile and foreskin epithelia has depicted how female-to-male transmission occurs [24]. These reports together provide important platform knowledge for designing mucosal HIV vaccines. Further analysis sheds light on the potential effector mechanisms of HIV Abs in the mucosal sites. A recent study has indicated a correlation of the Fc region glycosylation profiles of antiHIV Abs with its binding to MUC16, the most abundant type of mucin in the reproductive mucosa, suggesting that the resultant stabilization profile of anti-HIV Abs can directly modify the patterns of in situ mucosal infection as well as phagocytosis and/or virion transfer across mucosal sites [25]. This finding may provide potential explanation for the protective correlates of IgG instead of IgA responses in the RV144 trial; that is, Fc effector functions of certain IgG subclasses might have more predominant influence than the bivalent antiviral activity of IgA dimers. Thus the Ab-related environmental milieu within the mucosa could affect mucosal HIV infection, and its optimization for HIV protection may need unexpected patterns of effector function modulation (Fig. 42.1). Current studies analyzing residual viral genomes in homogenized tissues of passively NAb-immunized macaques by ultrasensitive polymerase chain reaction methods have suggested that evaluation of mucosa-associated virological parameters is critical for defining HIV protection [26,27]. Finally, a recent work revisiting protective correlates of live-attenuated nef-deleted SIV vaccines has indicated that mucosal oligomeric gp41-specific IgG induced by nef-deleted SIV infection could be a protective factor in blockade of wild-type SIV challenge [28]. Another report

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FIGURE 42.1 Modes of Ab-based protection against mucosal HIV infection. Anti-HIV Abs, including neutralizing Abs (NAbs), can exert a vast array of protective mechanisms against mucosal HIV infection, which should be taken into account for rational design of an Ab-based HIV vaccine.

has found robust Ab affinity maturation evoked by live-attenuated nef-deleted SIV vaccines [29], implying the potential contribution of mucosal anti-HIV Ab responses to HIV protection. Altogether, we need to take a vast array of factors into consideration for development of a vaccine inducing effective mucosal anti-HIV Abs.

III. MUCOSAL VACCINES INDUCING HIV-SPECIFIC T CELL RESPONSES A. Mucosal HIV Infection in the Acute Phase Toward Systemic Infection Sexual transmission of HIV occurs via the intrarectal or intravaginal route, followed by massive acute depletion of HIV-targeted

memory CD41 T cells in the gut mucosal tissues [30 32]. Involvement of dendritic cells (DCs) in mucosal HIV transmission has been indicated (Fig. 42.2). Langerhans-cell-like DC subsets and plasmacytoid DCs in the mucosal epithelium that express HIV receptors, CD4 and CCR5, and are susceptible to HIV infection can be the first targets for HIV infection [33,34]. HIV replication in DCs is not efficient, but HIV transmission from HIV-infected DCs to CD41 T cells could trigger efficient acute HIV proliferation. Alternatively, HIV captured by mucosal DCs via C-type lectin such as DC-SIGN is transmitted to CD41 T cells, facilitating efficient acute HIV proliferation [35,36]. Such DC-mediated HIV transmission results in massive HIV replication and severe depletion of memory CCR51 CD41 T cells in gut mucosal lymphoid tissues in the acute

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FIGURE 42.2 Modes of T-cellbased control of mucosal HIV replication.

phase [30 32]. This rapid CD41 T cell depletion in gut mucosal tissues impairs adaptive immune response and damages mucosal epithelium barrier, leading to chronic immune activation with persistent HIV replication in HIV-infected individuals [37]. Mucosal HIVspecific T cell responses may be the front line against acute mucosal HIV replication and rapid HIV dissemination [38]. Indeed, a previous report has indicated higher levels of mucosal T cells with higher functionality in HIV elite controllers [39]. Induction of effective mucosal T cell responses is thus considered to be important for the control of acute mucosal HIV replication and systemic HIV spread as well as the protection of HIV transmission (Fig. 42.1). Mucosal T cell responses have been analyzed in macaque AIDS models of SIV or SHIV infection. In particular, the SIV infection model played a central role in demonstrating massive depletion of memory CD41 T cells by virus infection in gut mucosal tissues in the acute phase of infection [30 32]. Repeated intrarectal low-dose SIV/SHIV challenges have been used for evaluation of vaccine efficacy against mucosal transmission [40].

Live attenuated nef-deleted SIV vaccines, although not applicable to clinical use, to safety concerns, have been intensively examined because they can confer protection against wildtype pathogenic SIV challenge [41]. In macaques infected with live attenuated nef-deleted SIV, control of nef-deleted SIV replication is not complete but partial, resulting in induction of persistent T cell responses in mucosal tissues. These T cell responses have been indicated to contribute to consistent protection from mucosal wild-type SIV challenge [42], implying the rationale for development of a vaccine inducing effective mucosal anti-HIV T cell responses.

B. Viral Vectors for Mucosal Anti-HIV T Cell Responses Optimization of vaccine delivery and immunogen is crucial for the development of an effective HIV vaccine. Recent studies have indicated the potential of several viral vectors to induce mucosal viral antigen-specific T cell responses as vaccine-delivery tools. Adenovirus (Ad) vectors have been widely used for induction of HIV/SIV antigen-specific

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T cell response. Clinical trials using recombinant Ad serotype 5 (Ad5) vectors failed to show efficacy and indicated the large inhibitory effect of preexisting anti-Ad5 Abs on vaccine immunogenicity [43,44]. Other serotype-derived Ad vectors that are less affected by preexisting antivector Abs in humans have been developed for efficient HIV-specific T cell responses [45,46]. Intramuscular Ad5/Ad26 vector vaccination has been shown to induce efficient T cell responses in intestine, vagina, and lung mucosal tissues as well as in peripheral lymphocytes in macaques [47,48]. Induction of T cell responses in mucosal tissues by intramuscular Ad26 vector vaccination has also been confirmed in a clinical trial [49]. Macaques orally immunized with aerosolized Ad5 vectors expressing SIV antigens showed efficient induction of SIVspecific T cell responses in the bronchoalveolar lavage and ameliorated CD41 T cell depletion in the intestine after intrarectal SIV challenge, compared to intramuscularly immunized animals [50]. Intramuscular and intrarectal immunization with Ad5 and chimpanzee Ad63 (ChAd63) vectors expressing SIV antigens has been indicated to reduce acquisition risk by repeated intrarectal low-dose SIV challenges in macaques [51] (Chapter 24: Recombinant Adenovirus Vectors as Mucosal Vaccines). Recombinant pox viruses such as modified vaccinia virus Ankara (MVA) and canarypox virus (CNPV) have been used as vaccinedelivery tools to induce mucosal T cell responses. Macaques intranasally immunized with DNAs coding full SIV genome, interleukin 2 (IL-2) and IL-15, and recombinant MVAs expressing SIV Gag, Pol, and Env showed efficient SIV-specific T cell induction in rectal mucosal tissues and slower AIDS progression than in intramuscularly immunized macaques [52]. The potential of intramuscular recombinant CNPV vector immunization to induce mucosal T cell responses was indicated in a clinical trial [16]. We have developed a vaccine using recombinant Sendai virus (SeV) vectors and have

shown the potential of this vector to efficiently induce antigen-specific T cell responses in macaques [53]. A phase 1 clinical trial has confirmed the safety and immunogenicity of the replication-competent SeV vector expressing HIV Gag [54]. Intranasal administration with recombinant SeV vectors efficiently induced T cell responses not only systemically, but also in the tonsil and local secondary lymphoid tissues proximal the nasal mucosa in macaques [55]. We have also detected T cell responses at the intestinal mucosa after intranasal SeV administration (unpublished data). These results indicate the potential of SeV vectors to induce mucosal T cell responses. The potential of rhesus cytomegalovirus (RhCMV) vectors to induce effective T cell responses against SIV challenge has been indicated in rhesus macaques [56]. Half of the animals vaccinated with recombinant RhCMV vectors were protected from mucosal pathogenic SIV challenge. Analysis implicated effector memory T cell responses induced by persistent RhCMV replication in this effective SIV protection. It has been reported that these SIV-specific CD81 T cells induced by RhCMV vectors target not canonical MHC-I-restricted epitopes but MHC-II or MHC-E-restricted epitopes [57].

C. Mucosal T Cell Responses Effective Against HIV Infection CD81 T cell responses are crucial for the control of HIV replication [58,59]. Individual viral antigen-specific CD81 T cells show different efficacy against virus replication, and optimization of vaccine immunogens is critical for induction of effective anti-HIV CD81 T cell responses. Dominant induction of ineffective T cell responses could inhibit induction of effective CD81 T cell responses. Cumulative studies have implicated CD81 T cell responses targeting HIV Gag and Vif in HIV control [53,60 62]. Currently, the HIVconsv

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REFERENCES

immunogen, consisting of multiple conserved regions of the HIV proteome [63], and the HTI immunogen, consisting of HIV Gag/Pol/Vif/ Nef-derived regions that were relatively conserved and targeted predominantly by individuals with reduced viral loads [64], have been proposed as optimized immunogen candidates for induction of effective CD81 T cell responses. CD41 T cell responses are crucial for effective CD81 T cell induction [65], but HIV/ SIV-specific CD41 T cells can be preferential targets for HIV infection [66]. Our recent study analyzing vaccine efficacy against intravenous SIV challenge in macaques has indicated that virus-specific CD107a2 CD41 T cell induction by vaccination did not lead to efficient CD41 T cell responses following infection, but rather accelerated viral replication in the acute phase [67]. It is therefore speculated that induction of mucosal HIV-specific CD41 T cells by vaccination may enhance acute HIV replication after mucosal HIV transmission. This suggests the benefit of avoiding virus-specific CD41 T cell induction in HIV vaccine design. CD81 T induction with the help of vector antigenspecific CD41 T cell responses by vaccination can be an effective strategy [68]. We have previously shown that passive polyclonal NAb immunization at day 7 after SIV infection results in induction of effective T cell responses, leading to long-term SIV control in rhesus macaques [69 71]. Analysis has indicated Ab-mediated enhancement of antigen uptake by DCs, followed by induction of Gagspecific polyfunctional CD41 T cell responses and increased in vitro viral suppressive activity in CD81 cells, suggesting synergism between Abs and T cells for the control of mucosal HIV/ SIV replication. This has been confirmed in a macaque model of SHIV infection by another group [72], indicating a possible benefit of the combination of Ab and T cell induction in HIV vaccine design.

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