Mechanisms of Immune Control in HIV-1 Virus Controllers

Abstract

There is a lack of a clear understanding of what constitutes a potent natural immune response capable of mediating post-infection protection in an HIV-1 infection setting. Thus, the goal of my dissertation was to dissect the immune responses to HIV-1 infection associated with protection using a model for natural control from HIV-1 infection. The first objective was to expand our understanding of what constitutes an effective CD8+ T cell response, while the second objective was to bridge Fab and Fc-mediated antibody effector functions associated with natural control of HIV-1 infection. The conventional T cell paradigm dictates CD8+ T cell recognition of peptides in the context of MHC class I. Remarkably, a paradigm shifting study demonstrated that induction of MHC class E and II-restricted CD8+ T cells was associated with the clearance of SIV infection in rhesus macaques. However, the induction of the unconventional class II-restricted CD8+ T cells in a natural HIV-1 infection setting, their ontogeny, distribution across different HIV-1 disease states and their role in viral control remain unclear. In the first part of my dissertation research, I hypothesized that HIV-1 specific class II-restricted CD8+ T cells are present in patients naturally controlling HIV-1 infection (Virus Controllers). I also hypothesized that HLA class II-restricted CD8+ T cells capable of suppressing viral replication in autologous CD4+ T cells are ‘ex-CD4+ T cells’ with CD8-like anti-viral effector functions.I not only showed that HIV-1 specific HLA class II-restricted CD8+ T cells are present in HIV-1 VCs, but that memory class II-restricted CD8+ T cell responses were more often detectable in VCs than in chronic viremics, and absent in healthy donors. I also demonstrated that VC CD8+ T cells inhibit virus replication in both a class I- and II-dependent manner and that in two VC patients the class II-restricted CD8+ T cells with an anti-viral gene signature expressed both CD4+ and CD8+ T cell lineage-specific genes. These data demonstrated that anti-viral memory class II-restricted CD8+ T cells with hybrid CD4+ and CD8+ features are present during natural HIV-1 infection. The presence of these atypical CD8+ T cells during HIV-1 infection redefines what may constitute an effective CD8+ T cell response. Moreover, my findings provide a potentially effective target for CD8+ T cell vaccine strategies given that these cells are readily detectable at a higher frequency in HIV+ patients spontaneously controlling virus replication compared to chronic patients.The second objective of my dissertation was to bridge the Fab-mediated neutralization and Fc-mediated humoral effector functions associated with natural control of HIV-1 infection by determining whether neutralization breadth was coordinated with the Fc effector function, antibody-dependent cellular phagocytosis (ADCP), in HIV-1 VCs. The Fc domain of antibodies enhances the in vivo neutralization potencies of broadly neutralization antibodies while the Fc effector functions antibody-dependent complement deposition (ADCD) and antibody-dependent cellular trogocytosis (ADCT) have been associated with the development of neutralization breadth. However, the potential coordination of ADCP, an Fc effector function associated with decreased infection risk and also enriched in HIV-1 VCs, with neutralization breadth and how such a relationship might mediate enhanced virus control remain unclear.In the second part of my dissertation research, I hypothesized that the development of nAb breadth was coordinated with ADCP breadth in HIV-1 VCs. I also hypothesized that the HIV-1 VC broadly neutralizing antibody (bNAb) polyclonal response targeted both known bNAb epitopes and previously unidentified vulnerable epitopes on the HIV-1 Envelope. By utilizing a novel polyclonal epitope mapping approach, I also hypothesized that the polyclonal antibody responses (neutralizing and non-neutralizing) to natural HIV-1 infection can be mapped by electron microscopy.I discovered a coordination between the nAb breadth and virion ADCP breadth in a subset of HIV-1 VCs characterized by the targeting of the CD4bs, V3 glycan and MPER known bNAb epitopes on the HIV-1 envelope that potentially act in synergy to mediate the broad nAb and ADCP responses observed in this patient cohort. The HIV-1 VCs with bNAb activity contain a potent class of CD4bs bNAbs that has never been reported in HIV-1 VCs without autoimmunity before. Thus, these findings not only suggest the presence of potent humoral responses in HIV-1 VCs, but also suggest a possible role of ADCP in modulating the bNAb response in a low viremia setting.Taken together, these findings highlight the presence of novel immune responses and multi-compartment associations in a subset of patients mediating natural control of viral infection and hence indicating the need to further investigate and elucidate the mechanistic processes behind these immune responses and relationships. This body of work sheds light on the complex anti-viral immune response in HIV-1 VCs and provides potential novel targets for future HIV vaccine design.