Abstract

Following completion of reverse transcription, the HIV cDNA becomes integrated into a host chromosome. For this to take place, the HIV """"""""preintegration complex"""""""" (PIC) must be transported to the location of the host chromosomes. For the case of multiplication of non-dividing cells, a characteristic of HIV, the PIC must pass through the host nuclear membrane to achieve integration. Dr. Bukrinsky has made a number of contribution in studies of subcellular sorting of PICs, and proposed to continue his studies in this renewal. Work will focus on the viral-encoded protein vpr. In a nuclear localization sequence (NLS) in MA protein and the vpr protein contribute karyophillic signals to the PIC. Extensive work by others has elucidated several of the proteins involved in nuclear localization, including karyopherins, proteins that function in part by binding NLS sequences. In this renewal, Dr. Bukrinsky proposes to: 1) characterize the Vpr-karyopherin alpha interaction; 2) investigate the effects of Vpr on interactions of karyopherins with MA and other NLS-containing proteins; 3) demonstrate the effect of Vpr on the process of nuclear import; and 4) determine the role of Vpr and Vpx in HIV-2/SIV nuclear import. The investigator has published extensively in this area and is familiar with many of the methods necessary to carry out the study.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI033776-06
Application #
2543339
Study Section
AIDS and Related Research Study Section 3 (ARRC)
Project Start
1993-07-01
Project End
2001-06-30
Budget Start
1998-07-01
Budget End
1999-06-30
Support Year
6
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
Picower Institute for Medical Research
Department
Type
DUNS #
City
Manhasset
State
NY
Country
United States
Zip Code
11030

  Publications

Levin, Aviad; Loyter, Abraham; Bukrinsky, Michael (2011) Strategies to inhibit viral protein nuclear import: HIV-1 as a target. Biochim Biophys Acta 1813:1646-53
Li, Ge; Elder, Robert T; Dubrovsky, Larisa et al. (2010) HIV-1 replication through hHR23A-mediated interaction of Vpr with 26S proteasome. PLoS One 5:e11371
Li, Ge; Bukrinsky, Michael; Zhao, Richard Y (2009) HIV-1 viral protein R (Vpr) and its interactions with host cell. Curr HIV Res 7:178-83
Iordanskiy, Sergey N; Bukrinsky, Michael I (2009) Analysis of viral and cellular proteins in HIV-1 reverse transcription complexes by co-immunoprecipitation. Methods Mol Biol 485:121-34
Iordanskiy, Sergey; Berro, Reem; Altieri, Maria et al. (2006) Intracytoplasmic maturation of the human immunodeficiency virus type 1 reverse transcription complexes determines their capacity to integrate into chromatin. Retrovirology 3:4
Haffar, Omar; Dubrovsky, Larisa; Lowe, Richard et al. (2005) Oxadiazols: a new class of rationally designed anti-human immunodeficiency virus compounds targeting the nuclear localization signal of the viral matrix protein. J Virol 79:13028-36
Iordanskiy, Sergey; Zhao, Yuqi; Dubrovsky, Larisa et al. (2004) Heat shock protein 70 protects cells from cell cycle arrest and apoptosis induced by human immunodeficiency virus type 1 viral protein R. J Virol 78:9697-704
Agostini, I; Popov, S; Li, J et al. (2000) Heat-shock protein 70 can replace viral protein R of HIV-1 during nuclear import of the viral preintegration complex. Exp Cell Res 259:398-403
Bukrinsky, M I; Haffar, O K (1999) HIV-1 nuclear import: in search of a leader. Front Biosci 4:D772-81
Haffar, O K; Smithgall, M D; Popov, S et al. (1998) CNI-H0294, a nuclear importation inhibitor of the human immunodeficiency virus type 1 genome, abrogates virus replication in infected activated peripheral blood mononuclear cells. Antimicrob Agents Chemother 42:1133-8

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