Empiric approaches to develop an effective AIDS vaccine have not been successful;indeed, the precise goals for a vaccine are unknown as the correlates of protection from infection and disease progression remain to be defined. Moreover, a major obstacle to design of an effective immunogen is the need to target diverse strains of HIV that are encountered worldwide. To address these issues, we have developed a collaborative research program at the center of the South African AIDS epidemic in KwaZulu Natal. This has allowed us to initiate simultaneous examination of viral, host genetic and immunologic factors that modulate acute and chronic HIV infection, and now allows us to expand these studies in large enough cohorts to be able to control for the diverse HLA types encountered in human populations. Such comprehensive and integrated data do not exist currently. Preliminary data already generated from South Africa suggest that the virus-host interaction is highly predictable, both in terms of epitopes targeted and the pathways to immune escape that are tolerated by the virus. With established mechanisms for over 95% successful longitudinal follow up of persons in this cohort, we are poised to define the precise epitopes targeted in acute and chronic infection associated with initial and persistent containment of viremia, and to determine the preferred mutations that arise at immunodominant epitopes targeted in clade C virus infection, which makes up the majority of global cases. Moreover, the proposed studies will allow us to define the adaptive virus-specific CD4 T+ cell response in clade C virus infection, and the role of these cells and the restricting class II alleles in disease pathogenesis. These issues are critical for HIV vaccine design and for understanding HIV pathogenesis. We propose to build on our solid preliminary data and outstanding functional collaborations to 1) Define the CD4+ and CD8+ T cell immune responses in persons with Clade C virus infection that contribute to containment of viremia, focusing on the most prevalent HLA alleles in Southern Africa, and persons with both acute and chronic infection;2) Define the evolution of clade C HIV under cellular immune selection pressure;3) Determine the impact of immune selection pressure on viral replicative fitness of clade C HIV infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI067073-05
Application #
7763243
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Sharma, Opendra K
Project Start
2006-02-01
Project End
2011-06-04
Budget Start
2010-02-01
Budget End
2011-06-04
Support Year
5
Fiscal Year
2010
Total Cost
$602,506
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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Hölzemer, Angelique; Thobakgale, Christina F; Jimenez Cruz, Camilo A et al. (2015) Selection of an HLA-C*03:04-Restricted HIV-1 p24 Gag Sequence Variant Is Associated with Viral Escape from KIR2DL3+ Natural Killer Cells: Data from an Observational Cohort in South Africa. PLoS Med 12:e1001900; discussion e1001900
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