Abstract

This proposal will investigate the contribution of nuclear transport activities of Vpr and Vpx proteins to primate lentiviral pathogenicity. In vitro studies will be used to identify domains required for nuclear localization of HIV-1 Vpr and SIV Vpx and for association of Vpr and Vpx with viral reverse transcription complexes, and to characterize the pathway through which nuclear localization is directed and examine the phenotype of nuclear import mutants in macrophage infection. In vivo studies in rhesus macaques will be used to examine the relative fitness of selected SIV Vpx mutants, which are impaired in nuclear import.
The specific aims are: 1) identify effector domains for nuclear localization of HIV-1 Vpr and SIV Vpx and for association of Vpr/Vpx with viral reverse transcription complexes; 2) characterize the pathway through which nuclear localization of Vpr/Vpx proteins is directed and identify the potential role of bridging proteins in the interaction of Vpr/Vpx with the nuclear import apparatus; 3) examine the phenotype of nuclear import mutants of HIV-1 and SIV in macrophage infection; 4) examine the relative in vivo fitness of SIV Vpx mutants which are altered in nuclear import. It is expected that these studies will more fully define the contribution of nuclear import activities of Vpr and Vpx to virus replication in vitro and in vivo.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI037475-13
Application #
7051427
Study Section
Special Emphasis Panel (NSS)
Program Officer
Sharma, Opendra K
Project Start
1995-05-01
Project End
2010-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
13
Fiscal Year
2006
Total Cost
$396,703
Indirect Cost

  Institution

Name
University of Massachusetts Medical School Worcester
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655

  Publications

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
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
Fletcher 3rd, T M; Brichacek, B; Sharova, N et al. (1996) Nuclear import and cell cycle arrest functions of the HIV-1 Vpr protein are encoded by two separate genes in HIV-2/SIV(SM). EMBO J 15:6155-65