PATHOGENESIS OF A CCR2B TROPIC R SIV-RCM IN MACAQUES

Aaron Diamond Aids Research Center, New York NY

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Abstract

We propose to construct a CCR2b-tropic recombinant SIV (rSIV) to study its transmission and pathogenesis in macaques. This proposal is based on our recent finding of a unique SIVrcm strain in West Africa. Because SIVrcm is the only primate lentivirus identified thus far that uses neither CCR5 nor CXCR4 but CCR2b as a coreceptor, we plan to further study the function of the viral envelope in vivo. First, we will construct an rSIVrcm by replacing the env gene of the pathogenic molecular clone SIVmac239 with the counterpart of SIVrcm. Second, we will compare the biological properties of the rSIVrcm to its parental SIVrcm and SIVmac239 strains. Third, we will study viral transmission and pathogenesis after inoculating a replication-competent rSIVrcm into macaques via vaginal, rectal and intravenous routes. For the latter, we will determine: 1) which route will confer productive infection and if the transmission is mediated by CD4+/CCR2+ cells; 2) changes in biological and genetic properties of the recovered virus through transmission and over time; 3) viral dissemination and tropism; 4) pathological effects in peripheral cells and lymph tissues using flow cytometry, immunohistochemistry and in situ hybridization techniques; 5) correlation between viral load and disease development using a quantitative PCR assay; and 6) clinical signs of AIDS-like disease.