We are utilizing a candidate gene approach to identify polymorphic loci that may have a role in viral infection and disease progression. Identification of such loci provides a valuable tool for the identification of host-cellular components that are operative in viral infection, replication, viral assembly, and immune regulation of the infection. Defining the mechanisms by which host factors restrict viral disease process will advance our understanding of viral pathogenesis and may lead to possible therapuetic interventions. Differences in mutation frequencies between ethnic/racial groups may also explain at least in part the geographical variation observed for both HIV and hepatitis B virus (HBV). To date we have established nearly 6000 cell lines from participants enrolled in natural history cohorts of the three major HIV risk groups, hemophiliacs, homosexuals, and intravenous drug users. We have also initiated cohort studies to investigate the role of host genetic factors in hepatitis C virus (HCV) and HBV clearance and pathology. Our approach has been: 1) establish cell lines from study participants as a renewable source of DNA; 2) identify single nucleotide polymorphisms (SNPs) or insertion/deletion (indel) mutations in candidate genes; 3) screen SNPs in large cohorts and in cases and controls; and 4) use categorical and survival analyses to test for associations between genotypes and phenotype.To date our group has contributed to the identification of 6 genes that affect infection, the rate of progression to AIDS, and specific AIDS outcomes. Several variants in genes involved in immune response to HIV, viral transcription, and viral assembly have been identified by our group which also have been shown to delay or accelerate progression to AIDS. Although the effect of each of these variants is small, together they account for approximately 30-50% of long-term AIDS survivors. Using the genetic analysis of HIV-1 as a model for association analysis of complex diseases which have both genetic and environmental components, we are employing a similar strategy to investigate the host genetic contributions to outcomes following infection with the hepatitis viruses, HCV and HBV. These important human viral infections have global distributions and extremely high prevalence rate in some regions of the world and among certain risk groups and cause considerable morbidity and mortality. They are also associated with increased risk of liver cancer, and have similar, although not identical, risk factors. The pathogenic effects of these viruses are highly variable and not fully explained by strain differences or subtypes. We are using a candidate gene approach to elucidate the genetic basis for the extensive variation observed within risk groups in viral clearance, liver disease progression, and resistance to infection for these important pathogens. Identification of Candidate Gene Polymorphisms Associated with AIDS - candidate genes, gene mapping, Genetic Susceptibility, HIV, microsatellites, - Human Tissues, Fluids, Cells, etc.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC010297-02
Application #
6289362
Study Section
Special Emphasis Panel (LGD)
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
An, Ping; Thio, Chloe L; Kirk, Gregory D et al. (2008) Regulatory polymorphisms in the interleukin-18 promoter are associated with hepatitis C virus clearance. J Infect Dis 198:1159-65
Li, Xing; Gold, Bert; O'hUigin, Colm et al. (2007) Unique features of TRIM5alpha among closely related human TRIM family members. Virology 360:419-33
Guo, Xiu Chan; Scott, Kevin; Liu, Yan et al. (2006) Genetic factors leading to chronic Epstein-Barr virus infection and nasopharyngeal carcinoma in South East China: study design, methods and feasibility. Hum Genomics 2:365-75
Javanbakht, Hassan; An, Ping; Gold, Bert et al. (2006) Effects of human TRIM5alpha polymorphisms on antiretroviral function and susceptibility to human immunodeficiency virus infection. Virology 354:15-27
Modi, William S; Lautenberger, James; An, Ping et al. (2006) Genetic variation in the CCL18-CCL3-CCL4 chemokine gene cluster influences HIV Type 1 transmission and AIDS disease progression. Am J Hum Genet 79:120-8
Guo, Xiu-Chan; O'Brien, Stephen J; Winkler, Cheryl et al. (2006) [Association study of chromosome 4 STRs polymorphisms with nasopharyngeal carcinoma] Yi Chuan 28:783-90
Walsh, Emily C; Sabeti, Pardis; Hutcheson, Holli B et al. (2006) Searching for signals of evolutionary selection in 168 genes related to immune function. Hum Genet 119:92-102
Song, Byeongwoon; Gold, Bert; O'Huigin, Colm et al. (2005) The B30.2(SPRY) domain of the retroviral restriction factor TRIM5alpha exhibits lineage-specific length and sequence variation in primates. J Virol 79:6111-21
Modi, W S; Scott, K; Goedert, J J et al. (2005) Haplotype analysis of the SDF-1 (CXCL12) gene in a longitudinal HIV-1/AIDS cohort study. Genes Immun 6:691-8
Duggal, Priya; Winkler, Cheryl A; An, Ping et al. (2005) The effect of RANTES chemokine genetic variants on early HIV-1 plasma RNA among African American injection drug users. J Acquir Immune Defic Syndr 38:584-9

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