The ability of HIV-1 to cause a productive infection in target cells is tightly linked to host mechanisms regulated by cellular activation. The vast majority of HIV-1 targets, CD4+ T cells, are normally in a resting state in vivo and hence are resistant to infection. However, in infected individuals there is a high viral replication and T cell turnover throughout the infection. It is not clear what activation signals and host factors generate a continuous supply of T cell targets that sustain the high viral loads in vivo. The long-term objective of this application is to decipher the cellular and molecular signals that regulate HIV- 1 life cycle within its physiological targets. Our central hypothesis is that HIV- 1 exploits antigen-independent signals, provided to resting T cells by cytokines and antigen-presenting cells such as dendritic cells, to establish a productive infection. Our published and preliminary results present evidence for this hypothesis, by demonstrating that the IL-2 family of cytokine signals promotes HIV- 1 infection in resting primary T cells. A key feature in these studies is the use of primary human T cells, rather than transformed cell lines, to characterize viral-host interplay at the molecular level. In this application we propose: 1) To identify additional antigen-independent signals that facilitate HIV-l infection of resting T cells. 2) To delineate the molecular mechanisms by which these signals recruit resting T cells as HIV-l targets. 3) The role of HIV-1 Nef in modulating primary T cell activation state and how this affects amplifying antigen-independent recruitment of bystander T cells for HIV-l infection. 4) To determine the role of antigen-independent signals and viral products in affecting the survival of primary T cells. We anticipate that the knowledge gained from these studies will provide a framework to understand the virus-host interplay in vivo and may have implications to develop novel therapeutic strategies against host factors that regulate HIV- 1 infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI049131-05
Application #
6891068
Study Section
Special Emphasis Panel (ZRG1-AARR-1 (01))
Program Officer
Plaeger, Susan F
Project Start
2001-05-01
Project End
2007-04-30
Budget Start
2005-05-01
Budget End
2007-04-30
Support Year
5
Fiscal Year
2005
Total Cost
$302,000
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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