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 K. Axthelm, Norman L. Letvin, Joseph Sodroski

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    65 Scopus citations

    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 - Jun 9 2001

    ASJC Scopus subject areas

    • Microbiology
    • Immunology
    • Insect Science
    • Virology

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    Etemad-Moghadam, B., Rhone, D., Steenbeke, T., Sun, Y., Manola, J., Gelman, R., Fanton, J. W., Racz, P., Tenner-Racz, K., Axthelm, M. K., Letvin, N. L., & 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, 75(12), 5646-5655. https://doi.org/10.1128/JVI.75.12.5646-5655.2001