): A major goal of vaccine research for prevention of AIDS is to determine the immune correlates of protection against HIV-1 infection. In this context, our proposal seeks to understand how HLA-A*1101 (HLA-A11), a significantly prevalent class I MHC molecule in a cohort of Thai Highly Exposed Persistently Seronegative (HEPS) brothel workers, and the most common HLA-A locus allele in South East Asia (SEA), functions in relation to protective immunity to HIV-1 infection. Our hypothesis is that it may relate, at least in part, to the way this class I allele binds cytotoxic T lymphocyte (CTL) epitopes and presents them to T cell receptors (TCRs). To test this hypothesis, we propose a biochemical and crystallographic analysis of HLA-A11 complexed with single HIV-1 peptides. These peptides will be selected based on results from our CTL studies in Thai HLA-A11-positive HIV-infected and HEPS individuals. The HIV-A11-restricted epitopes which are immunodominant in both of these donor groups, and conserved between the predominant North American clade B and major Thai clade E strains of HIV-1, will be the initial focus of these studies. Since CD8+ CTLs play a critical role in the initial immune responses to HIV-1 infection, a molecular characterization of HLA-A11 complexed with immunodominant HIV-1 peptides is important and relevant to understand the nature of HLA-A11-restricted CTL responses in these cohorts. The long-term objective of this study is to identify natural mechanisms potentially able to confer resistance to HIV-1 infection and provide a structural framework for the design of peptide-based HIV-1 vaccines capable of reproducing these apparent protective states of immunity. Knowledge derived from these studies will therefore be useful in relation to HIV-1 infection and other infectious diseases prevalent in SEA where this allele is extremely common.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI046309-01A1
Application #
6147604
Study Section
Special Emphasis Panel (ZRG1-AARR-2 (01))
Program Officer
Bradac, James A
Project Start
2000-07-01
Project End
2002-06-30
Budget Start
2000-07-01
Budget End
2001-06-30
Support Year
1
Fiscal Year
2000
Total Cost
$177,500
Indirect Cost
Name
University of Connecticut
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
City
Storrs-Mansfield
State
CT
Country
United States
Zip Code
06269
Li, Lenong; Chen, Weifeng; Bouvier, Marlene (2005) A biochemical and structural analysis of genetic diversity within the HLA-A*11 subtype. Immunogenetics 57:315-25
Li, Lenong; Bouvier, Marlene (2004) Structures of HLA-A*1101 complexed with immunodominant nonamer and decamer HIV-1 epitopes clearly reveal the presence of a middle, secondary anchor residue. J Immunol 172:6175-84
Li, Lenong; Promadej, Nattawan; McNicholl, Janet M et al. (2002) Crystallization and preliminary X-ray crystallographic studies of HLA-A*1101 complexed with an HIV-1 decapeptide. Acta Crystallogr D Biol Crystallogr 58:1195-7