Current areas of investigation include ADCC as a mechanism of protection against human and simian immunodeficiency viruses, the effects of KIR and MHC class I polymorphisms on NK cell responses to virus-infected cells, and mechanisms of lentiviral resistance to tetherin/BST-2.
Recent studies from our lab have contributed to our understanding of the role of antibody-dependent cell-mediated cytotoxicity (ADCC) in immunodeficiency virus infection. We developed an assay for measuring the ability of antibodies to direct the killing of HIV-1- and SIV-infected cells expressing physiologically relevant conformations of the viral envelope glycoprotein (Alpert et al. J. Virol. 2012). For its sensitivity, broad dynamic range and reproducibility, this assay was selected as one of six primary variables for the immune correlates analysis of the RV144 (or “Thai trial”) vaccine trial (Haynes et al. N. Engl. J. Med. 2012). Using this assay, we found also that the time-dependent maturation of complete protection in macaques immunized with nef-deleted, live-attenuated SIV is associated with progressive increases in ADCC activity against the challenge virus (Alpert et al. PLoS Pathog. 2012). More recently, we reported a correlation between ADCC and virus neutralization by HIV-1 envelope (Env)-specific monoclonal antibodies (von Bredow et al. J. Virol. 2016), which indicates, perhaps not surprisingly, that most antibodies that are capable of binding to functional Env trimers on virions to block infectivity are also able to bind to Env on the surface of virus-infected cells to direct their elimination by ADCC.
Natural killer (NK) cells recognize and kill virus-infected cells and tumors without prior antigenic stimulation, and thus provide an important innate defense against viral infections and cancers. NK cell responses in primates are regulated in part through interactions between two highly polymorphic sets of molecules, the killer-cell immunoglobulin-like receptors (KIRs) on NK cells and their MHC class I ligands on target cells. A number of studies have linked KIR and HLA class I polymorphisms to differences in the ability to control HIV-1 infection; however, functional studies to address the significance of KIR-MHC class I interactions on NK cell responses have been limited by the lack of defined ligands for KIRs in non-human primate models. We found that the binding of common MHC class I molecule in the rhesus macaque to an inhibitory KIR is stabilized by certain SIV peptides, but not by others (Colantonio et al. PLoS Pathog. 2011). We further demonstrated that SIV peptides that stabilize KIR-MHC class I interactions suppress the degranulation of primary NK cells (Schafer et al. PLoS Pathog. 2015), consistent with the possibility that HIV-1 and SIV may acquire changes in viral epitopes that increase the binding of MHC class I ligands to inhibitory KIRs as a mechanism of immune evasion.
Tetherin (BST-2 or CD317) is an interferon-inducible transmembrane protein that interferes with the detachment of enveloped viruses from infected cells. We identified Nef as the viral gene product of SIV that counteracts restriction by tetherin in Old World monkeys, and found that this activity is dependent on a five amino acid sequence that is missing from the cytoplasmic domain of human tetherin (Jia & Serra-Moreno et al. PLoS Pathog. 2009). The absence of sequences in human tetherin that confer susceptibility to Nef explains why this activity was ultimately acquired by the Vpu and Env proteins of HIV-1 and HIV-2, respectively. We also identified compensatory changes in the cytoplasmic tail of Env that restore resistance to tetherin in a nef-deleted strain of SIV that regained a pathogenic phenotype in rhesus macaques (Serra-Moreno et al. Cell Host Microbe. 2011). This finding is consistent with the adaptation of HIV-2 Env for antagonism of human tetherin, and provides direct evidence that the ability to counteract restriction by tetherin is important for lentiviral pathogenesis. We additionally found that the HIV-1 Vpu protein protects virus-infected cells from ADCC as a function of its ability to prevent the accumulation of nascent virions on the cell surface by counteracting tetherin (Arias et al. 2014. PNAS. 2014). A direct implication of this finding is that tetherin serves as a link between innate and adaptive immunity to enhance the susceptibility of virus-infected cells to antibodies.