Antiviral Activity In Situ

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ABSTRACT_Project 3 Anti-HIV antibodies can interact with a variety of Fc-receptors (FcRs) that are differentially expressed on host effector cells and exert a broad range of functions including antibody-dependent cell phagocytosis (ADCP) and antibody-dependent cell mediated cytotoxcity (ADCC). Passive as well as active vaccination in human and non human primate (NHP) studies have indicated that ADCC as well as phagocytosis are consistent correlates of protection. However, testing of the mechanistic relevance of IgG subclasses and allotypes on antiviral activity remains extremely limited. FcR-bearing cells also have a broad distribution which can vary widely by cell type, tissue, and species, and remain incompletely characterized in NHP, particularly in mucosal sites of lentivirus transmission. Further, compartmental considerations on the relative contributions of ADCC and ADCP to interruption of early HIV and SIV replication remain underexplored. Importantly, we have demonstrated disparate expansion of transient and tissue-resident NK cells in both HIV and SIV infections, but the relevance of these populations, as well as tissue-resident or trafficking subpopulations of other FcR- bearing cells remains unclear. Defining the events that take place in these early mucosal foci will provide critical insights into functional interactions that inhibit ongoing virus replication and spread in a highly dynamic mucosal environment that includes a range of genetic variability of the IgG and FcR repertoires and the significant heterogeneity of NHP FcR compared to humans. This Project will explore the specific hypothesis that optimal antiviral antibody activity is impacted by the tissue distribution of effector cells and FcR expression, which can be tuned to enhance vaccine responses and subsequent protection against SHIV challenge. The specific aims for Project 3 are as follows: Aim 1: Define the In vivo recognition of SIV/SHIV-infected cells by antibody and FcR-bearing cells in the GI and FRT mucosae. Aim 2. Define the antiviral properties of human immunoglobulin subclasses in vivo. Aim 3. Define the relative contribution of FcR-bearing cells to protection against mucosal SHIV challenge.