The nuclear localization signal of the matrix protein of human immunodeficiency virus type 1 allows the establishment of infection in macrophages and quiescent T lymphocytes. (original) (raw)

• Journal List
• Proc Natl Acad Sci U S A
• v.91(15); 1994 Jul 19
• PMC44324

Proc Natl Acad Sci U S A. 1994 Jul 19; 91(15): 6992–6996.

Infectious Disease Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037-1099.

Abstract

Lentiviruses, including human immunodeficiency virus type 1 (HIV-1), are unusual among retroviruses in their ability to infect nondividing cells. The matrix proteins of several lentiviruses contain a short stretch of amino acids reminiscent of known nuclear localization signals. In HIV-1, this motif has been shown to function as a nuclear targeting sequence when conjugated to a heterologous protein, and to permit the active nuclear import of the HIV-1 preintegration complex in growth-arrested cells. In the present work, mutations were introduced in the matrix nuclear localization region of T-cell- and macrophage-tropic HIV-1 clones. The resulting viral mutants replicated with normal or even accelerated kinetics in dividing cells, including activated peripheral blood lymphocytes. However, in sharp contrast with wild-type virus, the mutants could not grow efficiently in terminally differentiated macrophages or establish a stable and inducible infection intermediate in unstimulated peripheral blood lymphocytes. Because macrophages represent a major viral reservoir in vivo, and because at any given time most T cells in the body are quiescent, these results strongly suggest that the karyophilic properties of the matrix protein are critical for the spread of the virus in HIV-infected individuals, and consequently for AIDS pathogenesis.

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• Humphries EH, Temin HM. Cell cycle-dependent activation of rous sarcoma virus-infected stationary chicken cells: avian leukosis virus group-specific antigens and ribonucleic acid. J Virol. 1972 Jul;10(1):82–87. [PMC free article] [PubMed] [Google Scholar]
• Humphries EH, Temin HM. Requirement for cell division for initiation of transcription of Rous sarcoma virus RNA. J Virol. 1974 Sep;14(3):531–546. [PMC free article] [PubMed] [Google Scholar]
• Lewis PF, Emerman M. Passage through mitosis is required for oncoretroviruses but not for the human immunodeficiency virus. J Virol. 1994 Jan;68(1):510–516. [PMC free article] [PubMed] [Google Scholar]
• Roe T, Reynolds TC, Yu G, Brown PO. Integration of murine leukemia virus DNA depends on mitosis. EMBO J. 1993 May;12(5):2099–2108. [PMC free article] [PubMed] [Google Scholar]
• Weinberg JB, Matthews TJ, Cullen BR, Malim MH. Productive human immunodeficiency virus type 1 (HIV-1) infection of nonproliferating human monocytes. J Exp Med. 1991 Dec 1;174(6):1477–1482. [PMC free article] [PubMed] [Google Scholar]
• Lewis P, Hensel M, Emerman M. Human immunodeficiency virus infection of cells arrested in the cell cycle. EMBO J. 1992 Aug;11(8):3053–3058. [PMC free article] [PubMed] [Google Scholar]
• Bukrinsky MI, Haggerty S, Dempsey MP, Sharova N, Adzhubel A, Spitz L, Lewis P, Goldfarb D, Emerman M, Stevenson M. A nuclear localization signal within HIV-1 matrix protein that governs infection of non-dividing cells. Nature. 1993 Oct 14;365(6447):666–669. [PMC free article] [PubMed] [Google Scholar]
• Kalderon D, Roberts BL, Richardson WD, Smith AE. A short amino acid sequence able to specify nuclear location. Cell. 1984 Dec;39(3 Pt 2):499–509. [PubMed] [Google Scholar]
• Bukrinsky MI, Sharova N, McDonald TL, Pushkarskaya T, Tarpley WG, Stevenson M. Association of integrase, matrix, and reverse transcriptase antigens of human immunodeficiency virus type 1 with viral nucleic acids following acute infection. Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):6125–6129. [PMC free article] [PubMed] [Google Scholar]
• Sharova N, Bukrinskaya A. p17 and p17-containing gag precursors of input human immunodeficiency virus are transported into the nuclei of infected cells. AIDS Res Hum Retroviruses. 1991 Mar;7(3):303–306. [PubMed] [Google Scholar]
• Kim SY, Byrn R, Groopman J, Baltimore D. Temporal aspects of DNA and RNA synthesis during human immunodeficiency virus infection: evidence for differential gene expression. J Virol. 1989 Sep;63(9):3708–3713. [PMC free article] [PubMed] [Google Scholar]
• von Schwedler U, Song J, Aiken C, Trono D. Vif is crucial for human immunodeficiency virus type 1 proviral DNA synthesis in infected cells. J Virol. 1993 Aug;67(8):4945–4955. [PMC free article] [PubMed] [Google Scholar]
• Hwang SS, Boyle TJ, Lyerly HK, Cullen BR. Identification of the envelope V3 loop as the primary determinant of cell tropism in HIV-1. Science. 1991 Jul 5;253(5015):71–74. [PubMed] [Google Scholar]
• Kornbluth RS, Oh PS, Munis JR, Cleveland PH, Richman DD. Interferons and bacterial lipopolysaccharide protect macrophages from productive infection by human immunodeficiency virus in vitro. J Exp Med. 1989 Mar 1;169(3):1137–1151. [PMC free article] [PubMed] [Google Scholar]
• Trono D, Feinberg MB, Baltimore D. HIV-1 Gag mutants can dominantly interfere with the replication of the wild-type virus. Cell. 1989 Oct 6;59(1):113–120. [PubMed] [Google Scholar]
• Stevenson M, Stanwick TL, Dempsey MP, Lamonica CA. HIV-1 replication is controlled at the level of T cell activation and proviral integration. EMBO J. 1990 May;9(5):1551–1560. [PMC free article] [PubMed] [Google Scholar]
• Bukrinsky MI, Stanwick TL, Dempsey MP, Stevenson M. Quiescent T lymphocytes as an inducible virus reservoir in HIV-1 infection. Science. 1991 Oct 18;254(5030):423–427. [PMC free article] [PubMed] [Google Scholar]
• Zack JA, Haislip AM, Krogstad P, Chen IS. Incompletely reverse-transcribed human immunodeficiency virus type 1 genomes in quiescent cells can function as intermediates in the retroviral life cycle. J Virol. 1992 Mar;66(3):1717–1725. [PMC free article] [PubMed] [Google Scholar]
• Lu YL, Spearman P, Ratner L. Human immunodeficiency virus type 1 viral protein R localization in infected cells and virions. J Virol. 1993 Nov;67(11):6542–6550. [PMC free article] [PubMed] [Google Scholar]
• Zack JA, Arrigo SJ, Weitsman SR, Go AS, Haislip A, Chen IS. HIV-1 entry into quiescent primary lymphocytes: molecular analysis reveals a labile, latent viral structure. Cell. 1990 Apr 20;61(2):213–222. [PubMed] [Google Scholar]
• Gao WY, Cara A, Gallo RC, Lori F. Low levels of deoxynucleotides in peripheral blood lymphocytes: a strategy to inhibit human immunodeficiency virus type 1 replication. Proc Natl Acad Sci U S A. 1993 Oct 1;90(19):8925–8928. [PMC free article] [PubMed] [Google Scholar]
• Bukrinsky MI, Sharova N, Dempsey MP, Stanwick TL, Bukrinskaya AG, Haggerty S, Stevenson M. Active nuclear import of human immunodeficiency virus type 1 preintegration complexes. Proc Natl Acad Sci U S A. 1992 Jul 15;89(14):6580–6584. [PMC free article] [PubMed] [Google Scholar]
• Garcia-Bustos J, Heitman J, Hall MN. Nuclear protein localization. Biochim Biophys Acta. 1991 Mar 7;1071(1):83–101. [PubMed] [Google Scholar]

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