The major objective of my laboratory is to identify host factors that contribute to infectious and other complex diseases. The tremendous impact of infectious diseases on global health, and the association of many human pathogens with common cancers, call for multiple research strategies to elucidate the mechanisms of infection and pathogenesis. Our strategy is to search for genetic variants that differentially affect rates of infection, or the course of pathogenesis, and which thereby identify the gene containing the variant as participating in the process of infection or pathogenesis, increasing knowledge of the mechanisms of pathogenesis and pointing to targets for therapeutic intervention. Our focus has been to discover genetic factors modulating HIV-1, HCV, and HBV infections and associated diseases. To this end, we have developed international collaborations to establish case-control and cohort studies in China and southern Africa to investigate HIV-1, HBV, and HCV as well as the common carcinomas, NPC and HCC, associated with the EBV and HB viruses, respectively. We have established a collaboration with the Botswana Harvard Partnership to investigate the genetic correlates of HIV-1 infection, progression, and response to antiretroviral therapy in a region severely impacted by HIV-1 subtype C infection, the subtype responsible for the majority of HIV-1 infections globally. Using both candidate gene and genome wide association approaches, we have employed high throughput genotyping technologies, including Illumina and Affymetrix, to discover genes associated with HIV-1-associated nephropathy and with progression to AIDS. Whenever a significant association is observed, the laboratory uses fine mapping to identify putative causal alleles and functional assays to assess effects on gene transcription and protein levels. Accomplishments: APOBEC3G is a human innate resistance factor to HIV-1 that is incorporated into budding virions. We previously have shown that polymorphism in the gene encoding APOBEC3G is associated with rate of progression to AIDS and trajectory of CD4+ T cell decline in HIV-1-infected persons. APOBEC3G, in the absence of HIV-1 encoded viral infectivity factor (vif), causes hypermutation of the nascent cDNA, effectively preventing viral integration and competent infection. Human APOBEC3Gs anti-HIV-1 activity is, however, disarmed by HIV-1 vif by interaction with proteins, including Cullin5 (CUL5), in the ubiquitination pathway leading to the degradation of APOBEC3G. Through a study of HIV-1 natural history cohorts with different clinical outcomes, we discovered that variant alleles and haplotype clusters in CUL5 influences the rate of CD4+ T-cell depletion. One intronic SNP that alters transcription binding efficiency is associated with 2.5-fold more rapid progression to AIDS. This finding highlights the importance of CUL5 in the degradation pathway of APOBEC3G and suggests that CUL5 may be a target for drug development. TRIM5 has recently been identified as a key retrovirus restriction factor and in the Rhesus macaque provides a complete restriction to HIV-1 infection post entry but before proviral integration. The mechanism for this restriction is believed to result from the action of TRIM5 protein on the viral capsid causing its premature disassemble and degradation via a ubiquitination pathway. Human Trim5 also has a modest effect on restricting HIV-1. We have completed a comprehensive survery of the extent of genetic variation and haplotype structure of the TRIM5 gene in European and African Americans, Asians, and the Xhosa from South African. We have also shown that three SNPs (1 promoter and 2 nonsynonymous SNPs) were associated with altered susceptibility to HIV-1 infection. To extend our investigation of host proteins that interact with viral capsid we did a comprehensive genetic analysis of the extent of polymorphism in PPIA, encoding cyclophilin A (CypA). CypA, a member of the family of cyclophillins that possess peptidyl-prolyl cis-trans isomerase activity, is incorporated into the HIV-1 viron capsid prior to budding and promotes HIV-1 infectivity by facilating capsid uncoating. In a genetic association study, we discovered that functional variants in the promoter region of PPIA s are associated with more rapid CD4+ T-cell loss and progression to AIDS, apparently by up-regulating PPIA expression. We also determined that there were no gene-gene interactions between TRIM5 and PPIA, although both encode host factors act on disassembly of the HIV-1 capsid. These findings may inform the rational design of a new class of anti-HIV therapeutics that target or mimic innate retroviral restriction factors such as APOBEC3G or TRIM5 and host factors such as CypA and CUL5 co-opted by HIV-1 for completion of its life cycle

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC010297-10
Application #
7592650
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
2007
Total Cost
$809,391
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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