"Identifying viral determinants of robust viral replication in non-human primate models of HIV-1 infection"
Current non-human primate models of pathogenic HIV-1 infection are limited by the inability to use HIV-1 as the challenge virus. SIV/HIV chimeric viruses have been developed to mimic HIV-1 infection in non-human primates. SHIVs that cause infection similar to HIV-1, characterized by robust viral replication and progression to disease, have been developed by expensive and labor-intensive methods involving serial passage of the viruses in vivo. I propose to define the viral determinants that enhance the ability of these adapted SHIVs to replicate in non-human primates.
Based on preliminary results, I hypothesize that one of the HIV-1 genes present in SHIVs: evn, vpu, tat, or rev, represents the viral determinant contributing to the replicative capacity of the virus in non-human primates. I propose to define the viral determinant using an in-vitro system by assessing the susceptibility of adapted and un-adapted SHIVs to treatment with type-l interferons, primary mediators of the early immune response to viral infection. In addition, I will serially passage susceptible SHIVs in-vitro in the presence of IFN in order to identify adaptive mutations facilitating robust replication.
Defining the viral determinants contributing to robust replication will inform the rational design of SHIVs that incorporate a minimal number of SIV genes. This study will also develop a system for adapting SHIVs to anti-viral host factors in vitro. The development of SHIVs that primarily incorporate HIV-1 genes and closely mimic pathogenic HIV-1 infection will improve the ability of assess the efficacy of antiretroviral therapies and vaccines for HIV-1.