Simian immunodeficiency viruses (SIV) cause a reproducible disease course in rhesus macaques identical in many aspects to HIV-1 infection in humans, including an acute phase characterized by high levels of viremia, reduction of viremia coincident with the onset of adaptive immune responses, a prolonged asymptomatic phase leading to a gradual decline in CD4+ T-cells and culminating in the development of opportunistic infections. SIVmac239 is a molecularly cloned, pathogenic isolate of SIV. SIVmac239 is resistant to antibody-mediated neutralization, either by SIV-positive animal plasma or by monoclonal antibodies directed against the viral envelope proteins, a property it also shares with clinically relevant, primary isolates of HIV- 1. Because of these phenotypic similarities, and access to a well-established animal model of AIDS pathogenesis, SIVmac239 is perfectly suited for molecular-genetic exploration of the relationship between antibody-resistance and the role of the antibody response in vivo.
The specific aims that constitute this proposal are unified by the goal of using the SIV/macaque model to bridge the divide between investigation of antibody-mediated neutralization in vitro and investigation of the biological consequences of the antibody response to infection in vivo. Experiments in specific aim #1 will focus on characterizing the antibody response in an infected rhesus macaque with an unusually high-titer neutralizing antibody response against SIVmac239.
In specific Aim #2, proposed experiments will test the hypothesis that infection induces antibodies that recruit antibody- dependent effector mechanisms, including antibody-dependent cellular cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC).
In specific Aim #3 recombinant antibodies will be used to ask whether antibody-mediated effector mechanisms contribute to control of infection after mucosal challenge. These experiments will improve our understanding of the biological mechanisms by which the antibody response to lentiviral infection contributes to control (or lack thereof) of viral replication, with an eye towards the rational design of vaccine immunogens and the development of therapeutic antibodies for passive immunoprophylaxis. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI057039-05
Application #
7417840
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Embry, Alan C
Project Start
2003-06-15
Project End
2010-04-30
Budget Start
2008-05-01
Budget End
2009-04-30
Support Year
5
Fiscal Year
2008
Total Cost
$425,509
Indirect Cost
Name
Harvard University
Department
Veterinary Sciences
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
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