In contrast to HIV-infected individuals, sooty mangabeys (SMs), an African monkey species that is a natural host for SIV, live an apparently normal lifespan in captivity despite many years of SIV infection. Although SMs are typically infected with a highly replicating virus, only a subset (10-15%) display moderate to severe CD4+ T cell depletion and, in fact, the development of an AIDS-like illness is very rare.
The aim of this project is to understand how SIV-infected SMs maintain CD4+ T cell homeostasis and avoid progression to AIDS. We will perform comparative studies of SIV-infected SMs with normal and depleted CD4+ T cell compartments. Pathogenic SIV infection of rhesus macaques (RMs), a non-natural host Asian monkey species, will also be used as a comparative model. The proposed studies will test three fundamental hypotheses that may explain why SIV infection of SMs is significantly less pathogenic than HIV infection of humans and SIV infection of RMs: (i) the average lifespan of virus infected cells is longer (and/or the fraction of virus produced by long-lived cells is higher);(ii) the infection is associated with lower levels of T cell turnover;and (iii) the virus infects a more limited subset of CD4+ T cells. The results of these studies will improve our understanding of the mechanisms underlying the lack of disease in SIV-infected SMs. These conceptual advances may provide insights for the pathogenesis of HIV infection in humans and may translate into the design of more effective treatments for AIDS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI066998-06
Application #
7740204
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Embry, Alan C
Project Start
2005-12-15
Project End
2010-05-31
Budget Start
2009-12-01
Budget End
2010-05-31
Support Year
6
Fiscal Year
2010
Total Cost
$304,212
Indirect Cost
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Chahroudi, Ann; Silvestri, Guido; Lichterfeld, Mathias (2015) T memory stem cells and HIV: a long-term relationship. Curr HIV/AIDS Rep 12:33-40
Chowdhury, Ankita; Silvestri, Guido (2013) Host-pathogen interaction in HIV infection. Curr Opin Immunol 25:463-9
Evans, David T; Silvestri, Guido (2013) Nonhuman primate models in AIDS research. Curr Opin HIV AIDS 8:255-61
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Schmökel, Jan; Li, Hui; Shabir, Asma et al. (2013) Link between primate lentiviral coreceptor usage and Nef function. Cell Rep 5:997-1009
Francella, Nicholas; Gwyn, Sarah E; Yi, Yanjie et al. (2013) CD4+ T cells support production of simian immunodeficiency virus Env antibodies that enforce CD4-dependent entry and shape tropism in vivo. J Virol 87:9719-32
Pandrea, Ivona; Parrish, Nicholas F; Raehtz, Kevin et al. (2012) Mucosal simian immunodeficiency virus transmission in African green monkeys: susceptibility to infection is proportional to target cell availability at mucosal sites. J Virol 86:4158-68
Chahroudi, Ann; Bosinger, Steven E; Vanderford, Thomas H et al. (2012) Natural SIV hosts: showing AIDS the door. Science 335:1188-93
Taaffe, Jessica E; Bosinger, Steven E; Del Prete, Gregory Q et al. (2012) CCR5 blockade is well tolerated and induces changes in the tissue distribution of CCR5+ and CD25+ T cells in healthy, SIV-uninfected rhesus macaques. J Med Primatol 41:24-42
Bosinger, Steven E; Jacquelin, Beatrice; Benecke, Arndt et al. (2012) Systems biology of natural simian immunodeficiency virus infections. Curr Opin HIV AIDS 7:71-8

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