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J. Biol. Chem., Vol. 279, Issue 49, 51545-51553, December 3, 2004

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Macrophage Tropism of HIV-1 Depends on Efficient Cellular dNTP Utilization by Reverse Transcriptase^*

Tracy L. Diamond, Mikhail Roshal, Varuni K. Jamburuthugoda¶, Holly M. Reynolds, Aaron R. Merriam, Kwi Y. Lee, Mini Balakrishnan¶, Robert A. Bambara¶||, Vicente Planelles**, Stephen Dewhurst||, and Baek Kim

From the Department of Microbiology and Immunology, ^¶Department of Biochemistry and Biophysics, and ^||Cancer Center, University of Rochester Medical Center, Rochester, New York 14642 and ^**Department of Pathology, School of Medicine, University of Utah, Salt Lake City, Utah 84132

Retroviruses utilize cellular dNTPs to perform proviral DNA synthesis in infected host cells. Unlike oncoretroviruses, which replicate in dividing cells, lentiviruses, such as human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus, are capable of efficiently replicating in non-dividing cells (terminally differentiated macrophages) as well as dividing cells (i.e. activated CD4+ T cells). In general, non-dividing cells are likely to have low cellular dNTP content compared with dividing cells. Here, by employing a novel assay for cellular dNTP content, we determined the dNTP concentrations in two HIV-1 target cells, macrophages and activated CD4+ T cells. We found that human macrophages contained 130-250-fold lower dNTP concentrations than activated human CD4+ T cells. Biochemical analysis revealed that, unlike oncoretroviral reverse transcriptases (RTs), lentiviral RTs efficiently synthesize DNA even in the presence of the low dNTP concentrations equivalent to those found in macrophages. In keeping with this observation, HIV-1 vectors containing mutant HIV-1 RTs, which kinetically mimic oncoretroviral RTs, failed to transduce human macrophages despite retaining normal infectivity for activated CD4+ T cells and other dividing cells. These results suggest that the ability of HIV-1 to infect macrophages, which is essential to establishing the early pathogenesis of HIV-1 infection, depends, at least in part, on enzymatic adaptation of HIV-1 RT to efficiently catalyze DNA synthesis in limited cellular dNTP substrate environments.

Received for publication, July 28, 2004 , and in revised form, September 22, 2004.

^* This work was supported by National Institutes of Health Research Grants AI49781 (to B. K.), P01 MH64570 and S11 NS43499 (to S. D.), GM49573 (to R. A. B.), and AI49057 (to V. P.) and Training Grant T32 AI49815 (to M. R. and T. L. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

To whom correspondence should be addressed: Dept. of Microbiology and Immunology, University of Rochester, 601 Elmwood Ave., Box 672, Rochester, NY 14642. Tel.: 585-275-6916; Fax: 585-473-9573; E-mail: baek_kim{at}urmc.rochester.edu.

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