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Journal of Virology, June 2001, p. 5646-5655, Vol. 75, No. 12
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.12.5646-5655.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

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,1 Daniela Rhone,2 Tavis Steenbeke,2 Ying Sun,1 Judith Manola,3 Rebecca Gelman,3 John W. Fanton,4 Paul Racz,5 Klara Tenner-Racz,5 Michael K. Axthelm,4 Norman L. Letvin,2 and Joseph Sodroski1,6,*

Department of Cancer Immunology and AIDS1 and Department of Biostatistical Sciences,3 Dana-Farber Cancer Institute, Department of Pathology, Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center,2 Harvard Medical School, and Department of Immunology and Infectious Diseases, Harvard School of Public Health,6 Boston, Massachusetts 02115; Oregon Regional Primate Research Center, Beaverton, Oregon 97006-34994; and Department of Pathology and Korber Laboratory, Bernhard-Nocht Institute for Tropical Medicine, Hamburg, Germany 203595

Received 17 November 2000/Accepted 16 March 2001

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.

* Corresponding author. Mailing address: Dana-Farber Cancer Institute, 44 Binney St., JFB 824, Boston, MA 02115. Phone: (617) 632-3371. Fax: (617) 632-4338. E-mail: joseph_sodroski{at}dfci.harvard.edu.

Journal of Virology, June 2001, p. 5646-5655, Vol. 75, No. 12
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.12.5646-5655.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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