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Journal of Virology, September 2001, p. 8063-8073, Vol. 75, No. 17
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.17.8063-8073.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Susceptibility of Rat-Derived Cells to Replication by Human Immunodeficiency Virus Type 1

Oliver T. Keppler,1 Wesley Yonemoto,1 Frank J. Welte,1 Kathryn S. Patton,1,dagger Demetris Iacovides,2 Robert E. Atchison,1,Dagger Tuan Ngo,1 David L. Hirschberg,3,§ Roberto F. Speck,1,|| and Mark A. Goldsmith1,4,*

Gladstone Institute of Virology and Immunology1 and Departments of Physiology2 and Medicine,4 School of Medicine, University of California San Francisco, San Francisco, California 94141-9100, and Department of Neurology and Neurological Sciences, Stanford University, Stanford, California 943053

Received 5 April 2001/Accepted 2 June 2001

Progress in developing a small animal model of human immunodeficiency virus type 1 (HIV-1) disease would greatly facilitate studies of transmission, pathogenesis, host immune responses, and antiviral strategies. In this study, we have explored the potential of rats as a susceptible host. In a single replication cycle, rat cell lines Rat2 and Nb2 produced infectious virus at levels 10- to 60-fold lower than those produced by human cells. Rat-derived cells supported substantial levels of early HIV-1 gene expression, which was further enhanced by overexpression of human cyclin T1. Rat cells displayed quantitative, qualitative, and cell-type-specific limitations in the late phase of the HIV-1 replication cycle including relative expression levels of HIV-1 Gag proteins, intracellular Gag processing, and viral egress. Nb2 cells were rendered permissive to HIV-1 R5 viruses by coexpression of human CD4 and CCR5, indicating that the major restriction on HIV-1 replication was at the level of cellular entry. We also found that primary rat lymphocytes, macrophages, and microglia expressed considerable levels of early HIV-1 gene products following infection with pseudotyped HIV-1. Importantly, primary rat macrophages and microglia, but not lymphocytes, also expressed substantial levels of HIV-1 p24 CA and produced infectious virions. Collectively, these results identify the rat as a promising candidate for a transgenic small animal model of HIV-1 infection and highlight pertinent cell-type-specific restrictions that are features of this species.

* Corresponding author. Mailing address: 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.

dagger Present address: Dynavax Technologies Corporation, Berkeley, CA 94710.

Dagger Present address: Rigel Pharmaceuticals, Inc., South San Francisco, CA 94080.

§ Present address: Agilent Technologies, Palo Alto, CA 94304.

|| Present address: University Hospital Zürich, CH-8091 Zürich, Switzerland.

Journal of Virology, September 2001, p. 8063-8073, Vol. 75, No. 17
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.17.8063-8073.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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