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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Special Emphasis Panel (ZRG5-ARRG (01))
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University of Massachusetts Medical School Worcester
Other Basic Sciences
Schools of Medicine
United States
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Brandano, Laura; Stevenson, Mario (2012) A highly conserved residue in the C-terminal helix of HIV-1 matrix is required for envelope incorporation into virus particles. J Virol 86:2347-59
Kaushik, Rajnish; Zhu, Xiaonan; Stranska, Ruzena et al. (2009) A cellular restriction dictates the permissivity of nondividing monocytes/macrophages to lentivirus and gammaretrovirus infection. Cell Host Microbe 6:68-80
Sharova, Natalia; Wu, Yuanfei; Zhu, Xiaonan et al. (2008) Primate lentiviral Vpx commandeers DDB1 to counteract a macrophage restriction. PLoS Pathog 4:e1000057
Zielske, Steven P; Stevenson, Mario (2006) Modest but reproducible inhibition of human immunodeficiency virus type 1 infection in macrophages following LEDGFp75 silencing. J Virol 80:7275-80
Zielske, Steven P; Stevenson, Mario (2005) Importin 7 may be dispensable for human immunodeficiency virus type 1 and simian immunodeficiency virus infection of primary macrophages. J Virol 79:11541-6
Triques, Karine; Stevenson, Mario (2004) Characterization of restrictions to human immunodeficiency virus type 1 infection of monocytes. J Virol 78:5523-7
Chiu, Ya-Lin; Cao, Hong; Jacque, Jean-Marc et al. (2004) Inhibition of human immunodeficiency virus type 1 replication by RNA interference directed against human transcription elongation factor P-TEFb (CDK9/CyclinT1). J Virol 78:2517-29
Somasundaran, Mohan; Sharkey, Mark; Brichacek, Beda et al. (2002) Evidence for a cytopathogenicity determinant in HIV-1 Vpr. Proc Natl Acad Sci U S A 99:9503-8
Sleigh, R; Sharkey, M; Newman, M A et al. (1998) Differential association of uracil DNA glycosylase with SIVSM Vpr and Vpx proteins. Virology 245:338-43
Hirsch, V M; Sharkey, M E; Brown, C R et al. (1998) Vpx is required for dissemination and pathogenesis of SIV(SM) PBj: evidence of macrophage-dependent viral amplification. Nat Med 4:1401-8

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