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

doi:10.1128/JVI.75.17.8063-8073.2001

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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^, Demetris Iacovides,² Robert E. Atchison,¹^, 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 facilitatestudies of transmission, pathogenesis, host immune responses,and antiviral strategies. In this study, we have explored thepotential of rats as a susceptible host. In a single replicationcycle, rat cell lines Rat2 and Nb2 produced infectious virus atlevels 10- to 60-fold lower than those produced by human cells.Rat-derived cells supported substantial levels of early HIV-1gene expression, which was further enhanced by overexpressionof human cyclin T1. Rat cells displayed quantitative, qualitative,and cell-type-specific limitations in the late phase of the HIV-1replication cycle including relative expression levels of HIV-1Gag proteins, intracellular Gag processing, and viral egress.Nb2 cells were rendered permissive to HIV-1 R5 viruses by coexpressionof human CD4 and CCR5, indicating that the major restriction onHIV-1 replication was at the level of cellular entry. We alsofound that primary rat lymphocytes, macrophages, and microgliaexpressed considerable levels of early HIV-1 gene products followinginfection with pseudotyped HIV-1. Importantly, primary rat macrophagesand microglia, but not lymphocytes, also expressed substantiallevels of HIV-1 p24 CA and produced infectious virions. Collectively,these results identify the rat as a promising candidate for atransgenic small animal model of HIV-1 infection and highlightpertinent cell-type-specific restrictions that are features ofthisspecies.

^* Corresponding author. Mailing address: Gladstone Institute of Virology and Immunology, P.O. Box 419100, San Francisco, CA94141. Phone: (415) 695-3775. Fax: (415) 695-1364. E-mail: mgoldsmith{at}gladstone.ucsf.edu.

Present address: Dynavax Technologies Corporation, Berkeley, CA94710.

Present address: Rigel Pharmaceuticals, Inc., South San Francisco, CA94080.

^§ Present address: Agilent Technologies, Palo Alto, CA94304.

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

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