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.

Agency
National Institute of Health (NIH)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI095985-04
Application #
8704244
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
Zeng, Ming; Smith, Anthony J; Shang, Liang et al. (2016) Mucosal Humoral Immune Response to SIVmac239∆nef Vaccination and Vaginal Challenge. J Immunol 196:2809-18
Barouch, Dan H; Ghneim, Khader; Bosche, William J et al. (2016) Rapid Inflammasome Activation following Mucosal SIV Infection of Rhesus Monkeys. Cell 165:656-67
Tartaglia, Lawrence J; Chang, Hui-Wen; Lee, Benjamin C et al. (2016) Production of Mucosally Transmissible SHIV Challenge Stocks from HIV-1 Circulating Recombinant Form 01_AE env Sequences. PLoS Pathog 12:e1005431
Martinez-Navio, José M; Fuchs, Sebastian P; Pedreño-López, Sònia et al. (2016) Host Anti-antibody Responses Following Adeno-associated Virus-mediated Delivery of Antibodies Against HIV and SIV in Rhesus Monkeys. Mol Ther 24:76-86
Larocca, Rafael A; Abbink, Peter; Peron, Jean Pierre S et al. (2016) Vaccine protection against Zika virus from Brazil. Nature 536:474-8
Stephenson, Kathryn E; Neubauer, George H; Bricault, Christine A et al. (2016) Antibody Responses After Analytic Treatment Interruption in Human Immunodeficiency Virus-1-Infected Individuals on Early Initiated Antiretroviral Therapy. Open Forum Infect Dis 3:ofw100
Stephenson, Kathryn E; D'Couto, Helen T; Barouch, Dan H (2016) New concepts in HIV-1 vaccine development. Curr Opin Immunol 41:39-46
Billingsley, James M; Rajakumar, Premeela A; Connole, Michelle A et al. (2015) Characterization of CD8+ T cell differentiation following SIVΔnef vaccination by transcription factor expression profiling. PLoS Pathog 11:e1004740
Adnan, Sama; Colantonio, Arnaud D; Yu, Yi et al. (2015) CD8 T cell response maturation defined by anentropic specificity and repertoire depth correlates with SIVΔnef-induced protection. PLoS Pathog 11:e1004633
Barouch, Dan H; Alter, Galit; Broge, Thomas et al. (2015) Protective efficacy of adenovirus/protein vaccines against SIV challenges in rhesus monkeys. Science 349:320-4

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