Analogies between the pathogenesis of clade B HIV-1 and other subtypes have been proposed but not proven, and the immunopathogenesis in non-B subtype HIV-1 infection remains inadequately explored. Cellular immunity in HIV-1 infection is believed to play a key role in viral control, and remains an important focus in vaccine development, in a region of the world where non-clade B infections predominate, it is crucial to characterize the immunopathogenesis of these viruses, because it is unclear whether they may elicit different immune responses and thus require different preventive and therapeutic approaches. Another geographic issue is the differential frequency of HLA alleles in different ethnic populations. Structured treatment interruptions (STI) of antiretroviral therapy (ARV) in the U.S. and Europe (where clade B predominates) have provided a unique opportunity to evaluate the role of cellular immune responses in the control of viremia. These studies have provided a model for the study of cellular immune control of viral replication in vivo. Until recently, such studies have not been feasible in many resource-poor settings where non-B clades predominate, particularly in Africa. Antiretroviral therapy has recently been introduced to Uganda, where two clinical studies evaluating ARV and STi, respectively, are currently ongoing at the Joint Clinical Research Centre in Kampala. These studies provide us a unique opportunity to evaluate the immune response in the setting of non-B clade HIV-1 infection and various ARV regimens. We hypothesize that the determinants antiviral cellular immunity could differ with the varying clades in distinct geographic regions. The goals of this proposal are to further dissect factors in non-B clade HIV infection, with potential implications in immunotherapeutics and vaccine development. Specifically, we propose: 1) To determine the T cell responses to clade A, and D viral strains in Uganda, in the context of the host HLA class alleles; 2) To perform mechanistic studies of antiviral function using CD8+ T cell clones; 3) To analyze the cellular immune responses in a cohort of Ugandan individuals Ireceiving continuous highly active antiretroviral therapy (HAART) and STI, and study the correlates of immune control in this population.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI043754-06
Application #
6889488
Study Section
Special Emphasis Panel (ZRG1-AARR-E (01))
Program Officer
D'Souza, Patricia D
Project Start
1999-04-01
Project End
2008-04-30
Budget Start
2005-05-01
Budget End
2006-04-30
Support Year
6
Fiscal Year
2005
Total Cost
$267,500
Indirect Cost
Name
Public Health Foundation Enterprises
Department
Type
DUNS #
082199324
City
City of Industry
State
CA
Country
United States
Zip Code
91746
Kityo, Cissy; Bousheri, Stephanie; Akao, Juliette et al. (2011) Therapeutic immunization in HIV infected Ugandans receiving stable antiretroviral treatment: a Phase I safety study. Vaccine 29:1617-23
Bousheri, Stephanie; Burke, Candace; Ssewanyana, Isaac et al. (2009) Infection with different hiv subtypes is associated with CD4 activation-associated dysfunction and apoptosis. J Acquir Immune Defic Syndr 52:548-52
Jones, Norman G; DeCamp, Allan; Gilbert, Peter et al. (2009) AIDSVAX immunization induces HIV-specific CD8+ T-cell responses in high-risk, HIV-negative volunteers who subsequently acquire HIV infection. Vaccine 27:1136-40
Eggena, Mark P; Hopkins, Heidi; Barugahare, Banson et al. (2006) CD4 T cell activation as a predictor for treatment failure in Ugandans with Plasmodium falciparum malaria. Am J Trop Med Hyg 74:41-3
Hanson, Andrea; Sarr, Abdoulaye Dieng; Shea, Amy et al. (2005) Distinct profile of T cell activation in HIV type 2 compared to HIV type 1 infection: differential mechanism for immunoprotection. AIDS Res Hum Retroviruses 21:791-8
Eggena, Mark P; Barugahare, Banson; Jones, Norman et al. (2005) Depletion of regulatory T cells in HIV infection is associated with immune activation. J Immunol 174:4407-14
Elrefaei, Mohamed; McElroy, Michael D; Preas, Christopher P et al. (2004) Central memory CD4+ T cell responses in chronic HIV infection are not restored by antiretroviral therapy. J Immunol 173:2184-9
Cao, H; Mani, I; Vincent, R et al. (2000) Cellular immunity to human immunodeficiency virus type 1 (HIV-1) clades: relevance to HIV-1 vaccine trials in Uganda. J Infect Dis 182:1350-6
Plymale, D R; Ng Tang, D S; Fermin, C D et al. (1995) Comparison of DNA fragmentation and color thresholding for objective quantitation of apoptotic cells. Scanning Microsc 9:833-42