The CD4+ T cells and macrophages represent the primary targets for infection with HIV-1. Replication of HIV-1 within macrophages plays a fundamental role in virus transmission, in the sequestration of HIV-1 in tissues, and in the maintenance of HIV-1 persistence during the progression of disease. Although macrophages are terminally differentiated and non-dividing cells, mitosis is not required for productive infection by lentiviruses, such as HIV-1, in contrast to onco-retroviruses which do require host cell mitosis for nuclear localization of viral DNA and provirus establishment. The infection of non-dividing cells by HIV-1 is governed by the association of virion-derived nucleophilic proteins with the viral genome, which facilitate nuclear localization of the viral genome in non-dividing cells. The Principal Investigator and his associates have shown that the nucleophilic virion protein Vpr remains associated with viral nucleic acids after virus infection and, as a consequence, facilitates nuclear localization of viral DNA in non-dividing cells. In this project, the Investigator proposes to characterize the mechanism by which Vpr and the related virion protein Vpx of HIV-2 and SIV determine nuclear localization of viral DNA and establish the provirus in non-dividing host cells. He and his associates will: (1) characterize determinants which govern nuclear localization of Vpr and Vpx and derive infectious molecular clones of HIV-1 and HIV-2 containing amino acid substitutions which preclude nuclear localization of Vpr and Vpx; (2) examine the replication phenotype of HIV-1 Vpr and HIV-2 Vpr/Vpx nuclear localization mutants in primary lymphocytes and macrophages, and the role of these proteins in nuclear targeting of viral DNA and in provirus establishment in these cell systems; and (3) identify the virion factors necessary for association of Vpr and Vpx with viral nucleic acids within the viral nucleoprotein preintegration complex.
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