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¹ Gladstone Institute of Virology and Immunology, School of Medicine, University of California at San Francisco, San Francisco, CA 94141
² Gladstone Institute of Cardiovascular Disease, School of Medicine, University of California at San Francisco, San Francisco, CA 94141
³ Department of Pathology, School of Medicine, University of California at San Francisco, San Francisco, CA 94141
⁴ Department of Medicine, School of Medicine, University of California at San Francisco, San Francisco, CA 94141
⁵ University of Massachusetts Medical School, Program in Molecular Medicine, Worcester, MA 01605
⁶ Howard Hughes Medical Institute, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016

Address correspondence to M.A. Goldsmith, Gladstone Institute of Virology and Immunology, P.O. Box 419100, San Francisco, CA 94141. Phone: 415-695-3775; Fax: 415-695-1364; E-mail: mgoldsmith{at}gladstone.ucsf.edu

The development of a permissive small animal model for the study of human immunodeficiency virus type (HIV)-1 pathogenesis and the testing of antiviral strategies has been hampered by the inability of HIV-1 to infect primary rodent cells productively. In this study, we explored transgenic rats expressing the HIV-1 receptor complex as a susceptible host. Rats transgenic for human CD4 (hCD4) and the human chemokine receptor CCR5 (hCCR5) were generated that express the transgenes in CD4⁺ T lymphocytes, macrophages, and microglia. In ex vivo cultures, CD4⁺ T lymphocytes, macrophages, and microglia from hCD4/hCCR5 transgenic rats were highly susceptible to infection by HIV-1 R5 viruses leading to expression of abundant levels of early HIV-1 gene products comparable to those found in human reference cultures. Primary rat macrophages and microglia, but not lymphocytes, from double-transgenic rats could be productively infected by various recombinant and primary R5 strains of HIV-1. Moreover, after systemic challenge with HIV-1, lymphatic organs from hCD4/hCCR5 transgenic rats contained episomal 2–long terminal repeat (LTR) circles, integrated provirus, and early viral gene products, demonstrating susceptibility to HIV-1 in vivo. Transgenic rats also displayed a low-level plasma viremia early in infection. Thus, transgenic rats expressing the appropriate human receptor complex are promising candidates for a small animal model of HIV-1 infection.

Key Words: HIV-1 • transgenic rats • CD4 • CCR5 • macrophages

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