Membrane-fusing capacity of the human immunodeficiency virus envelope proteins determines the efficiency of CD4+ T-cell depletion in macaques infected by a simian-human immunodeficiency virus

Bijan Etemad-Moghadam, Daniela Rhone, Tavis Steenbeke, Ying Sun, Judith Manola, Rebecca Gelman, John W. Fanton, Paul Racz, Klara Tenner-Racz, Michael Axthelm, Norman L. Letvin, Joseph Sodroski

    Research output: Contribution to journalArticle

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    Abstract

    The mechanism of the progressive loss of CD4+ T lymphocytes, which underlies the development of AIDS in human immunodeficiency virus (HIV-1)-infected individuals, is unknown. Animal models, such as the infection of Old World monkeys by simian-human immunodeficiency virus (SHIV) chimerae, can assist studies of HIV-1 pathogenesis. Serial in vivo passage of the nonpathogenic SHIV-89.6 generated a virus, SHIV-89.6P, that causes rapid depletion of CD4+ T lymphocytes and AIDS-like illness in monkeys. SHIV-KB9, a molecularly cloned virus derived from SHIV-89.6P, also caused CD4+ T-cell decline and AIDS in inoculated monkeys. It has been demonstrated that changes in the envelope glycoproteins of SHIV-89.6 and SHIV-KB9 determine the degree of CD4+ T-cell loss that accompanies a given level of virus replication in the host animals (G. B. Karlsson et. al., J. Exp. Med. 188:1159-1171, 1998). The envelope glycoproteins of the pathogenic SHIV mediated membrane fusion more efficiently than those of the parental, nonpathogenic virus. Here we show that the minimal envelope glycoprotein region that specifies this increase in membrane-fusing capacity is sufficient to convert SHIV-89.6 into a virus that causes profound CD4+ T-lymphocyte depletion in monkeys. We also studied two single amino acid changes that decrease the membrane-fusing ability of the SHIV-KB9 envelope glycoproteins by different mechanisms. Each of these changes attenuated the CD4+ T-cell destruction that accompanied a given level of virus replication in SHIV-infected monkeys. Thus, the ability of the HIV-1 envelope glycoproteins to fuse membranes, which has been implicated in the induction of viral cytopathic effects in vitro, contributes to the capacity of the pathogenic SHIV to deplete CD4+ T lymphocytes in vivo.

    Original languageEnglish (US)
    Pages (from-to)5646-5655
    Number of pages10
    JournalJournal of Virology
    Volume75
    Issue number12
    DOIs
    StatePublished - 2001

    Fingerprint

    Human Immunodeficiency Virus env Gene Products
    Simian Immunodeficiency Virus
    Human immunodeficiency virus
    Macaca
    T-lymphocytes
    HIV
    T-Lymphocytes
    Membranes
    proteins
    Glycoproteins
    glycoproteins
    Haplorhini
    HIV-1
    monkeys
    Human immunodeficiency virus 1
    Viruses
    Acquired Immunodeficiency Syndrome
    viruses
    Virus Replication
    virus replication

    ASJC Scopus subject areas

    • Immunology

    Cite this

    Membrane-fusing capacity of the human immunodeficiency virus envelope proteins determines the efficiency of CD4+ T-cell depletion in macaques infected by a simian-human immunodeficiency virus. / Etemad-Moghadam, Bijan; Rhone, Daniela; Steenbeke, Tavis; Sun, Ying; Manola, Judith; Gelman, Rebecca; Fanton, John W.; Racz, Paul; Tenner-Racz, Klara; Axthelm, Michael; Letvin, Norman L.; Sodroski, Joseph.

    In: Journal of Virology, Vol. 75, No. 12, 2001, p. 5646-5655.

    Research output: Contribution to journalArticle

    Etemad-Moghadam, B, Rhone, D, Steenbeke, T, Sun, Y, Manola, J, Gelman, R, Fanton, JW, Racz, P, Tenner-Racz, K, Axthelm, M, Letvin, NL & Sodroski, J 2001, 'Membrane-fusing capacity of the human immunodeficiency virus envelope proteins determines the efficiency of CD4+ T-cell depletion in macaques infected by a simian-human immunodeficiency virus', Journal of Virology, vol. 75, no. 12, pp. 5646-5655. https://doi.org/10.1128/JVI.75.12.5646-5655.2001
    Etemad-Moghadam, Bijan ; Rhone, Daniela ; Steenbeke, Tavis ; Sun, Ying ; Manola, Judith ; Gelman, Rebecca ; Fanton, John W. ; Racz, Paul ; Tenner-Racz, Klara ; Axthelm, Michael ; Letvin, Norman L. ; Sodroski, Joseph. / Membrane-fusing capacity of the human immunodeficiency virus envelope proteins determines the efficiency of CD4+ T-cell depletion in macaques infected by a simian-human immunodeficiency virus. In: Journal of Virology. 2001 ; Vol. 75, No. 12. pp. 5646-5655.
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    abstract = "The mechanism of the progressive loss of CD4+ T lymphocytes, which underlies the development of AIDS in human immunodeficiency virus (HIV-1)-infected individuals, is unknown. Animal models, such as the infection of Old World monkeys by simian-human immunodeficiency virus (SHIV) chimerae, can assist studies of HIV-1 pathogenesis. Serial in vivo passage of the nonpathogenic SHIV-89.6 generated a virus, SHIV-89.6P, that causes rapid depletion of CD4+ T lymphocytes and AIDS-like illness in monkeys. SHIV-KB9, a molecularly cloned virus derived from SHIV-89.6P, also caused CD4+ T-cell decline and AIDS in inoculated monkeys. It has been demonstrated that changes in the envelope glycoproteins of SHIV-89.6 and SHIV-KB9 determine the degree of CD4+ T-cell loss that accompanies a given level of virus replication in the host animals (G. B. Karlsson et. al., J. Exp. Med. 188:1159-1171, 1998). The envelope glycoproteins of the pathogenic SHIV mediated membrane fusion more efficiently than those of the parental, nonpathogenic virus. Here we show that the minimal envelope glycoprotein region that specifies this increase in membrane-fusing capacity is sufficient to convert SHIV-89.6 into a virus that causes profound CD4+ T-lymphocyte depletion in monkeys. We also studied two single amino acid changes that decrease the membrane-fusing ability of the SHIV-KB9 envelope glycoproteins by different mechanisms. Each of these changes attenuated the CD4+ T-cell destruction that accompanied a given level of virus replication in SHIV-infected monkeys. Thus, the ability of the HIV-1 envelope glycoproteins to fuse membranes, which has been implicated in the induction of viral cytopathic effects in vitro, contributes to the capacity of the pathogenic SHIV to deplete CD4+ T lymphocytes in vivo.",
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    AU - Rhone, Daniela

    AU - Steenbeke, Tavis

    AU - Sun, Ying

    AU - Manola, Judith

    AU - Gelman, Rebecca

    AU - Fanton, John W.

    AU - Racz, Paul

    AU - Tenner-Racz, Klara

    AU - Axthelm, Michael

    AU - Letvin, Norman L.

    AU - Sodroski, Joseph

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