The hallmark of HIV infection is the progressive decline in CD4+ T cells in the peripheral blood and the eventual collapse of the immune system, despite an apparently small number of HJ T-infected cells in this tissue. Despite intensive study, the mechanisms by which CD4+ cells are progressively lost are still unknown and hotly debated. However, the SIV/macaque model of HIV infection provides the opportunity to simultaneously examine the mechanisms of CD4+ T cell depletion and turnover in various tissue compartments, and at different stages of infection. Recent studies have demonstrated that rapid and profound depletion of CD4+ T cells occurs specifically within the intestine in the first few days of SIV infection, whereas minimal changes occur in peripheral lymphoid tissues at these time points. Additional studies demonstrated that this may be due to distinct phenotypic differences between CD4+ T cell subsets residing in mucosal and peripheral lymphoid tissues. The goals of the proposed studies are to determine how CD4+ T cells are lost throughout the course of SIV infection by simultaneously examining primary, peripheral, and mucosal lymphoid tissues at various stages of SlV infection and disease.
The specific aims are to; (1) Define the mechanisms of CD4+ T cell loss in SIV infection; by examining the relative contributions of cytotoxic T cell-mediated killing, apoptosis, CD4 antigen down regulation, and direct viral lysis to the overall loss of CD4+ T cells in various immunologic tissues. This will be accomplished by determining the effects of CD8 depletion on the CD4 T cell loss, quantifying SlV-specific CTLs in tissues throughout infection, and by multivariate flow cytometric analysis techniques to assess apoptosis, lysis and CD4 antigen down regulation in cells derived from primary, mucosal, and systemic lymphoid tissues, and; (2) Examine the rates of T cell turnover in primary, mucosal and peripheral lymphoid tissues in SIV infection; by determining the rates of both CD4 and CD8+ T cell proliferation at various stages of SlY infection. This will be accomplished by comparing levels of Ki-67 expression and rates of BrdUrd incorporation in CD4+ and CD8+ T cell subsets derived from various immunologic tissues. These studies will provide valuable information regarding the mechanisms of CD4+ T cell loss and turnover in HIV/SIV infection, and may provide answers to many of the mysteries involved in the pathogenesis of HIV/SIY infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
3R01AI049080-05S1
Application #
7285884
Study Section
AIDS and Related Research 8 (AARR)
Program Officer
Plaeger, Susan F
Project Start
2001-05-01
Project End
2008-04-30
Budget Start
2006-09-30
Budget End
2008-04-30
Support Year
5
Fiscal Year
2006
Total Cost
$216,757
Indirect Cost
Name
Tulane University
Department
Pathology
Type
Schools of Medicine
DUNS #
053785812
City
New Orleans
State
LA
Country
United States
Zip Code
70118
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Gill, Amy F; Ahsan, Muhammad H; Lackner, Andrew A et al. (2012) Hematologic abnormalities associated with simian immunodeficieny virus (SIV) infection mimic those in HIV infection. J Med Primatol 41:214-24
Xu, Huanbin; Wang, Xiaolei; Pahar, Bapi et al. (2012) Rapid down-regulation of ?c on T cells in early SIV infection correlates with impairment of T-cell function. FASEB J 26:2294-305
Wang, Xiaolei; Xu, Huanbin; Alvarez, Xavier et al. (2011) Distinct expression patterns of CD69 in mucosal and systemic lymphoid tissues in primary SIV infection of rhesus macaques. PLoS One 6:e27207
Xu, Huanbin; Wang, Xiaolei; Morici, Lisa A et al. (2011) Early divergent host responses in SHIVsf162P3 and SIVmac251 infected macaques correlate with control of viremia. PLoS One 6:e17965
Xu, Huanbin; Wang, Xiaolei; Pahar, Bapi et al. (2010) Increased B7-H1 expression on dendritic cells correlates with programmed death 1 expression on T cells in simian immunodeficiency virus-infected macaques and may contribute to T cell dysfunction and disease progression. J Immunol 185:7340-8
Wang, X; Xu, H; Gill, A F et al. (2009) Monitoring alpha4beta7 integrin expression on circulating CD4+ T cells as a surrogate marker for tracking intestinal CD4+ T-cell loss in SIV infection. Mucosal Immunol 2:518-26
Pahar, Bapi; Lackner, Andrew A; Piatak Jr, Michael et al. (2009) Control of viremia and maintenance of intestinal CD4(+) memory T cells in SHIV(162P3) infected macaques after pathogenic SIV(MAC251) challenge. Virology 387:273-84
Veazey, Ronald S; Acierno, Paula M; McEvers, Kimberly J et al. (2008) Increased loss of CCR5+ CD45RA- CD4+ T cells in CD8+ lymphocyte-depleted Simian immunodeficiency virus-infected rhesus monkeys. J Virol 82:5618-30

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