J. Exp. Med., Volume 188, Number 6, September 21, 1998 1159-1171

The Envelope Glycoprotein Ectodomains Determine the Efficiency of CD4⁺ T Lymphocyte Depletion in Simian- Human Immunodeficiency Virus-Infected Macaques

By Gunilla B. Karlsson,^* Matilda Halloran,^§ Dominik Schenten,^* Juliette Lee,^* Paul Racz, Klara Tenner-Racz, Judith Manola,^¶ Rebecca Gelman,^¶ Bijan Etemad-Moghadam,^* Elizabeth Desjardins,^* Richard Wyatt,^* Norma P. Gerard,^** Luisa Marcon,^* David Margolin, John Fanton,^§§ Michael K. Axthelm,^§§ Norman L. Letvin, and Joseph Sodroski^*

From the ^* Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115; the  Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts 02115; the ^§ Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115; the  Department of Pathology and Korber Laboratory, Bernhard-Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany; the ^¶ Department of Biostatistical Sciences, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115; the ^** Department of Medicine and Department of Pediatrics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115; the  Institute of Microbiology, University of Padua Medical School, Padua 35121, Italy; and the ^§§ Oregon Regional Primate Research Center, Beaverton, Oregon 97006-3499

CD4⁺ T lymphocyte depletion in human immunodeficiency virus type 1 (HIV-1)-infected humans underlies the development of acquired immune deficiency syndrome. Using a model in which rhesus macaques were infected with chimeric simian-human immunodeficiency viruses (SHIVs), we show that both the level of viremia and the structure of the HIV-1 envelope glycoprotein ectodomains individually contributed to the efficiency with which CD4⁺ T lymphocytes were depleted. The envelope glycoproteins of recombinant SHIVs that efficiently caused loss of CD4⁺ T lymphocytes exhibited increased chemokine receptor binding and membrane-fusing capacity compared with those of less pathogenic viruses. These studies identify the HIV-1 envelope glycoprotein ectodomains as determinants of CD4⁺ T lymphocyte loss in vivo and provide a foundation for studying pathogenic mechanisms.

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