The overall objectives are to extend understanding of the influence human major histocompatibility complex (HLA) and chemokine receptor (CCR) genes on the epidemiology (I.E. the acquisition and course) of HIV-1 infection. The project will draw upon 1) 450 seroconverters (SCs) and 100 highly exposed uninfected participants (EUs) in the Multicenter AIDS Cohort Study (MACS) as the population base for coordinated research on genetic determinants of both phenomena; and 2) a group of collaborators with wide expertise in HIV-1 epidemiology, immunogenetics, immunology, protein modeling, data management and biostatistics, and HLA statistical analysis. Particular advantage will be taken of the size and scope of the MACS as a unique epidemiologic resource for testing hypotheses about highly polymorphic gene projects identifiable by detailed molecular typing anywhere in the HLA region. HLA typing by SDCP, ARMS-SSP, and SSOP in dot-blot format will be distributed in four laboratories with capacities for verification by various techniques including fine-resolution automated sequencing. CCR5 and related work will employ the luciferase reporter assay, plasmid transfection, and cloning in conjunction with RT-PCR. The broad hypotheses are that 1) multiple, linked polymorphic HLA genes encoding products with distinctive structural characteristis interact to determine a substantial portion of the variation in the course of HIV-1 infection and probably also influence the initiation of HIV-1 infection and 2) co- receptor gene polymorphisms such as the 32-base-pair deletion in CCR5 tightly govern the initiation of infection and exercise discernible but less dramatic effects on its course. Validation of the many individual components of those hypotheses through extensive statistical analysis of genetic polymorphisms shown to influence acquisition and outcome of HIV-1 infection in sufficient numbers of appropriately selected subjects will lay the foundation for a comprehensive model of variable host response to HIV-1. Results of these genetic studies will be integrated into the MACs effort to examine virus replication rates and variation over time, immunopathogenetic phenomena such as T- cell homeostasis and CTL clonal evolution, natural history, and clinical outcomes. Elucidation of the genetic control of resistance/susceptibility to HIV-1 should help direct development of antiretroviral biologics (vaccines and immunomodulators) based on host and viral gene variation and could contribute to more general knowledge about genetic diversity in pathobiology.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI041951-03
Application #
2887597
Study Section
AIDS and Related Research Study Section 2 (ARRB)
Program Officer
Plaeger, Susan F
Project Start
1997-09-01
Project End
2001-08-31
Budget Start
1999-09-01
Budget End
2000-08-31
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Hu, L; Song, W; Brill, I et al. (2012) Genetic variations and heterosexual HIV-1 infection: analysis of clustered genes encoding CC-motif chemokine ligands. Genes Immun 13:202-5
Lazaryan, Aleksandr; Song, Wei; Lobashevsky, Elena et al. (2011) The influence of human leukocyte antigen class I alleles and their population frequencies on human immunodeficiency virus type 1 control among African Americans. Hum Immunol 72:312-8
Shrestha, Sadeep; Aissani, Brahim; Song, Wei et al. (2009) Host genetics and HIV-1 viral load set-point in African-Americans. AIDS 23:673-7
Tang, Jianming; Shao, Wenshuo; Yoo, Yun Joo et al. (2008) Human leukocyte antigen class I genotypes in relation to heterosexual HIV type 1 transmission within discordant couples. J Immunol 181:2626-35
Yoo, Yun Joo; Tang, Jianming; Kaslow, Richard A et al. (2007) Haplotype inference for present-absent genotype data using previously identified haplotypes and haplotype patterns. Bioinformatics 23:2399-406
Bansal, Anju; Yue, Ling; Conway, Joan et al. (2007) Immunological control of chronic HIV-1 infection: HLA-mediated immune function and viral evolution in adolescents. AIDS 21:2387-97
Shao, W; Tang, J; Song, W et al. (2007) CCL3L1 and CCL4L1: variable gene copy number in adolescents with and without human immunodeficiency virus type 1 (HIV-1) infection. Genes Immun 8:224-31
Shao, Wenshuo; Lazaryan, Aleksandr; Dorak, M Tevfik et al. (2006) Cohort- and time-specific associations of CTLA4 genotypes with HIV-1 disease progression. AIDS 20:1583-90
Lazaryan, Aleksandr; Lobashevsky, Elena; Mulenga, Joseph et al. (2006) Human leukocyte antigen B58 supertype and human immunodeficiency virus type 1 infection in native Africans. J Virol 80:6056-60
Wang, Chengbin; Tang, Jianming; Geisler, William M et al. (2005) Human leukocyte antigen and cytokine gene variants as predictors of recurrent Chlamydia trachomatis infection in high-risk adolescents. J Infect Dis 191:1084-92

Showing the most recent 10 out of 31 publications