Clinical progression rates among untreated HIV-infected patients and the clinical responses to antiretroviral therapy among treated patients are highly variable and only partially explained by plasma HIV RNA levels, suggesting that factors other than the extent of viral replication play a role in HIV pathogenesis. In vitro and animal models suggest that HIV causes widespread activation of CD4+ and CD8+ T cells, resulting in CD4+T cell depletion and immunodeficiency, and suggest a primary role of T cell activation in HIV pathogenesis. While higher levels of T cell activation are associated with more rapid clinical progression in HIV-infected patients, the biologic and clinical determinants of T cell activation in HIV infection remain poorly defined. In seeking a K23 Award, I am interested in exploring the role of virologic factors, host factors, and co-infections in determining T cell activation levels in HIV infection. I propose the following specific aims among HIVinfected patients: (1) to assess the association between virologic factors - including the extent of proviral HIV DNA in circulating cells, the extent of low-level viral replication, replicative capacity, and co-receptor tropism - and T cell activation; (2) to assess the association between host factors - including HLA haplotype and CCR5 polymorphisms - and T cell activation; (3) to assess the association between asymptomatic shedding of CMV and T cell activation; and (4) to assess whether valganciclovir treatment decreases T cell activation levels in a randomized controlled trial among HIV and CMV co-infected patients with sub-optimal immunologic responses to antiretroviral therapy. Understanding the potential causes of T cell activation may help identify targets for future immune-based interventions for many HIV-infected patients with suboptimal immunologic responses to antiretroviral therapy. To achieve these aims, I have assembled a mentoring committee of internationally recognized scientists with strong track records in translational research. These mentors span several relevant disciplines, including clinical research methods (Drs. Deeks and Jacobson), epidemiology and biostatistics (Dr. Martin), immunology (Dr. McCune), and virology (Dr. Wong). Their mentorship, as well as a focused training and research plan facilitated by a K23 award, will help me achieve my goal of developing an independent career in clinic-based translational research, focusing on questions relevant to the pathogenesis of HIV infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23AI065244-02
Application #
7049518
Study Section
AIDS Clinical Studies and Epidemiology Study Section (ACE)
Program Officer
Livnat, Daniella
Project Start
2005-04-15
Project End
2010-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
2
Fiscal Year
2006
Total Cost
$148,770
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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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
Appay, Victor; Fastenackels, Solène; Katlama, Christine et al. (2011) Old age and anti-cytomegalovirus immunity are associated with altered T-cell reconstitution in HIV-1-infected patients. AIDS 25:1813-22
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
Hunt, Peter W; Martin, Jeffrey N; Sinclair, Elizabeth et al. (2011) Valganciclovir reduces T cell activation in HIV-infected individuals with incomplete CD4+ T cell recovery on antiretroviral therapy. J Infect Dis 203:1474-83
Choi, Andy I; Lo, Joan C; Mulligan, Kathleen et al. (2011) Association of vitamin D insufficiency with carotid intima-media thickness in HIV-infected persons. Clin Infect Dis 52:941-4
Favre, David; Mold, Jeff; Hunt, Peter W et al. (2010) Tryptophan catabolism by indoleamine 2,3-dioxygenase 1 alters the balance of TH17 to regulatory T cells in HIV disease. Sci Transl Med 2:32ra36
Loke, P'ng; Favre, David; Hunt, Peter W et al. (2010) Correlating cellular and molecular signatures of mucosal immunity that distinguish HIV controllers from noncontrollers. Blood 115:e20-32

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