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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.

Key Words: simian–human immunodeficiency virus • Rhesus macaques • envelope glycoprotein • CD4⁺ T lymphocyte depletion • pathogenesis

Abbreviations used: CAT, chloramphenicol acetyltransferase; MIP, macrophage inflammatory protein; RT, reverse transcriptase; sCD4, human soluble CD4; SHIV, simian–human immunodeficiency virus; SIV, simian immunodeficiency virus.

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