The identification of host genetic factors provides a valuable tool for the identification of host cellular components that are operative in pathways leading to disease. Even genetic factors with small relative or attributable risks may be important since they suggest proteins and pathways that may provide targets for therapeutic intervention. However, the discovery of genes underpinning complex diseases requires large numbers of affected and unaffected cases and controls. Milestones reached this fiscal year include the completion of enrollment of 4000 participants for an investigation of the genetic correlates of Epstein-Barr-related nasal pharyngeal carcinoma in a high prevalence population and 2200 persons with hepatitis B virus infection, both in China.The genetic modifying roles of several genes involved in innate immunity in HIV-1 infection and pathogenesis was identified in our group using over 3000 HIV-1-exposed or infected persons enrolled in 5 natural history cohorts. Trim5 provides innate resistance to cross-species transmission of retroviruses. A polymorphism with functional consequence in the TRIM5 promoter was associated with increased risk of infection. APOBEC3G is an enzyme that hypermutates the nascent HIV DNA pre-integration. However, the antiviral activity of APOBEC3G is suppressed by HIV-1 viral infectivity factor and another human protein, Cullin 5 via a degradation pathway. Variants in the Cul5 gene are strongly associated with rapid loss of CD4 T cells. HIV-1 transmission is also influenced by chemokines; genetic variation in chemokines binding the HIV-1 CCR5 co-receptor have also been shown to influence HIV-1 transmission and HIV-1 progression to AIDS. These results strongly suggest that genetic variability explains in part the heterogeneity observed in human populations in susceptibility to HIV-1 infection and pathogenesis and may point to new targets for vaccine and drug development.
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