The greatest vulnerabilities in the life cycle of HIV to immunological intervention are the very early events following mucosal exposure to virus. In particular, nonhuman primate studies suggest antibody can abort or attenuate infection during this early stage but very little is known about how and where this is achieved. We hypothesize that antibody protection involves the complex interplay of antibody, virus, target cells and host immune cells. We further hypothesize that antibody may be involved at different stages of early infection including the earliest signaling events and that the presence of antibody may have profound effects on cellular and innate immune responses to the virus. We propose to investigate these hypotheses through detailed cross-sectional studies of SHIV-challenged macaques in the presence and absence of the broadly neutralizing antibody b12, which we have investigated extensively in the SHIV/macaque model of HIV infection. We propose to carry out serial necropsy studies combined with an arsenal of histological, virological, immunological, and systems biological approaches provided through this Program to reveal the details of antibody interception of virus.
The specific aims of the project are: 1 .To determine the course of dissemination of SHIV162P3 infection in macaques following high-dose vaginal challenge 2. To determine the anatomic sites and timing associated with complete antibody interception of the virus following SHIV challenge 3. To determine the anatomic sites, timing and sequelae associated with incomplete antibody interception of the virus following SHIV challenge 4. To determine the role of antibody effector function in interception of SHIV. The significance of this project is that it will provide a much clearer picture than hereto of how antibody prevents HIV infection. This is important for HIV vaccine design as it will influence the emphasis we place on particular immunization strategies, e.g. systemic versus mucosal immunization, and the characteristics of antibody that we try to induce.
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