Abstract

HIV-1 specific CTL appear to be crucial in the control of HIV-1 viral replication in vivo; in untreated individuals, a strong inverse correlation between circulating CTL frequency and plasma viral load has been observed. New combination antiretroviral therapies have dramatically decreased AIDS related mortality in the United States, and many acute and chronically infected individuals are being treated with these powerful antiretroviral agents. However, the impact of these therapies on the HIV-1 specific CTL response is unknown; The goal of this initial independent research project is to investigate the dynamics of HIV-1 specific CTL in HIV-1 infection.
In specific aim 1, the PI will examine the effect of drug treatment on the HIV-1 specific CTL response, whether effector and memory CTL decline in frequency following drug therapy, and whether this is related to time of initiation of treatment. The quality of the immune response will be assessed by analysis of the breadth of antigens recognized. Some patients entered on drug trials will not adhere to drug regimens due to adverse events or difficulties in compliance;
in specific aim 2, the quantity and kinetics of CTL change will be measured in relation to virus breakthrough. In addition, the PI will determine if breakthrough virus has escaped from CTL control. In a small number of patients who have controlled their plasma viremia after drug discontinuation the immune correlates of viral containment will be examined and the dynamics of CTL change in relation to viral load will be modeled. Finally, the PI and co-workers have observed a very high frequency of circulating CTL effectors in some long term non- progressors.
In specific aim 3 the number of CTL will be correlated with viral load using sensitive PCR techniques. These studies of CTL dynamics will likely contribute considerably to understanding the role of HIV-1 specific CTL and vaccine strategies designed to induce CTL in the context of a prophylactic anti-HIV-1 vaccine.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI044595-06
Application #
6632153
Study Section
Special Emphasis Panel (ZRG5-AARR-2 (01))
Program Officer
Livnat, Daniella
Project Start
1999-03-01
Project End
2005-02-28
Budget Start
2003-03-01
Budget End
2005-02-28
Support Year
6
Fiscal Year
2003
Total Cost
$352,032
Indirect Cost

  Institution

Name
J. David Gladstone Institutes
Department
Type
DUNS #
099992430
City
San Francisco
State
CA
Country
United States
Zip Code
94158

  Publications

Emu, Brinda; Moretto, Walter J; Hoh, Rebecca et al. (2014) Composition and function of T cell subpopulations are slow to change despite effective antiretroviral treatment of HIV disease. PLoS One 9:e85613
Hunt, Peter W; Landay, Alan L; Sinclair, Elizabeth et al. (2011) A low T regulatory cell response may contribute to both viral control and generalized immune activation in HIV controllers. PLoS One 6:e15924
Hunt, Peter W; Hatano, Hiroyu; Sinclair, Elizabeth et al. (2011) HIV-specific CD4+ T cells may contribute to viral persistence in HIV controllers. Clin Infect Dis 52:681-7
Hunt, Peter W; Cao, Huyen L; Muzoora, Conrad et al. (2011) Impact of CD8+ T-cell activation on CD4+ T-cell recovery and mortality in HIV-infected Ugandans initiating antiretroviral therapy. AIDS 25:2123-31
Kitchen, Christina M R; Yeghiazarian, Lilit; Hoh, Rebecca et al. (2011) Immune activation, CD4+ T cell counts, and viremia exhibit oscillatory patterns over time in patients with highly resistant HIV infection. PLoS One 6:e21190
Owen, Rachel E; Heitman, John W; Hirschkorn, Dale F et al. (2010) HIV+ elite controllers have low HIV-specific T-cell activation yet maintain strong, polyfunctional T-cell responses. AIDS 24:1095-105
Ferre, April L; Lemongello, Donna; Hunt, Peter W et al. (2010) Immunodominant HIV-specific CD8+ T-cell responses are common to blood and gastrointestinal mucosa, and Gag-specific responses dominate in rectal mucosa of HIV controllers. J Virol 84:10354-65
Ferre, April L; Hunt, Peter W; Critchfield, J William et al. (2009) Mucosal immune responses to HIV-1 in elite controllers: a potential correlate of immune control. Blood 113:3978-89
Jiang, Wei; Lederman, Michael M; Hunt, Peter et al. (2009) Plasma levels of bacterial DNA correlate with immune activation and the magnitude of immune restoration in persons with antiretroviral-treated HIV infection. J Infect Dis 199:1177-85
Hsue, Priscilla Y; Hunt, Peter W; Wu, Yuaner et al. (2009) Association of abacavir and impaired endothelial function in treated and suppressed HIV-infected patients. AIDS 23:2021-7

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