Our Science – An Website
Ping An, MD, MPH
Dr. An's primary interest is to uncover the genetic factors that confer host resistance or susceptibility to common infectious pathogens, especially HIV-1, hepatitis B virus (HBV), and hepatitis C virus (HCV).
Individuals responses to invading pathogens vary, ranging from complete resistance to increased susceptibility. The infection and progression of infectious diseases depend on the ecological and environmental factors as well as host genetic factors. Genetic restriction/susceptibility factors to viral diseases were the result of the interaction of virus and host defense developed during human evolutionary. Uncovering genetic association may lead to the identification of the host factors that play key roles in determining the outcome of virus-host interactions. Dr. An's work focuses on identifying the human genetic components that influence the disease susceptibility by using a population genetic epidemiology approach, in combination with evolutionary and functional analysis. A great number of host factors interact with HIV-1; however, their relative contribution is not clear due to complex interaction. Population genetic association study provides a way to assess the genes final impact on the disease outcome and to identify the most critical genes involved in pathogenesis.
To identify the host genetic factors associated with HIV-1/AIDS, we make use of five large US-based HIV-1 longitudinal cohorts, which were assembled before the effective anti-HIV treatment was available. The participants included those high risk exposed to HIV-1 but uninfected (HREU) and those that become infected during the study (seroconverters, SC) whose time of infection and progression to particular AIDS outcome is known. The frequency distribution of genetic variants in HREU and SC is compared to assess the impact on the risk of acquiring HIV-1 infection. The survival analysis is applied to assess the role of variants on disease progression from the time since HIV infection to AIDS outcomes: CD4 cell <200, AIDS defining conditions and AIDS-related death. Recently, with a candidate gene approach focusing on factors in the pathways of the regulation of HIV-1 life cycle, host immune response and innate defense, we have identified several genetic factors that influence HIV-1/ AIDS. (1) Chemokine and Chemokine receptors, including RANTES, IFNG, chemokine gene clusters, and chemokine receptor gene clusters. An intronic variant and its haplotype in RANTES, encoding a chemokine that blocks CCR5, was found to affect gene regulation and AIDS progression; a functional promoter variant in IFNG was shown to influence AIDS progression; a cluster of chemokine genes on 17q12 was associated with altered rate of AIDS progression; a cluster of chemokine receptor gene loci on 3p21 was also associated with AIDS progression. (2) Innate immunity factors, including TRIM5, APOBEC3G, and CUL5. Certain regulatory and nonsynonymous variants in TRIM5, whose rhesus version confers complete restriction to HIV-1, were found to affect human susceptibility to HIV-1 infection. A nonsynonymous variant in APOBEC3G, encoding a protein that intrinsically restrict HIV-1, was identified to accelerate disease progression. The variants and haplotype clusters in CUL5, encoding a protein that help HIV-1 vif degrade APOBEC3G, was associated with CD4 cell depletion in HIV-1 infected individuals. Dr. An is also studying the host genetic factors contributing to the infection of HBV and HCV.
This page was last updated on 3/28/2014.