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Journal of Virology, August 2001, p. 6776-6785, Vol. 75, No. 15
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.15.6776-6785.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Molecular Basis for Cell Tropism of CXCR4-Dependent Human Immunodeficiency Virus Type 1 Isolates

Kenzo Tokunaga,1 Michael L. Greenberg,2 Michael A. Morse,3 R. Ian Cumming,2 H. Kim Lyerly,2 and Bryan R. Cullen1,4,*

Department of Genetics,1 Department of Surgery,2 Department of Medicine,3 and the Howard Hughes Medical Institute,4 Duke University Medical Center, Durham, North Carolina 27710

Received 27 February 2001/Accepted 23 April 2001

Laboratory isolates of human immunodeficiency virus type 1 (HIV-1) that utilize CXCR4 as a coreceptor infect primary human macrophages inefficiently even though these express a low but detectable level of cell surface CXCR4. In contrast, infection of primary macrophages by primary CXCR4-tropic HIV-1 isolates is readily detectable. Here, we provide evidence suggesting that this difference in cell tropism results from a higher requirement for cell surface CXCR4 for infection by laboratory HIV-1 isolates. Transfected COS7 cells that express a high level of CD4 but a low level of CXCR4 were infected significantly more efficiently by two primary CXCR4-tropic HIV-1 isolates compared to the prototypic laboratory HIV-1 isolate IIIB. More importantly, overexpression of either wild-type or signaling-defective CXCR4 on primary macrophages dramatically enhanced the efficiency of infection by the laboratory HIV-1 isolate yet only modestly enhanced infection by either primary CXCR4-tropic virus. Overexpression of CD4 had, in contrast, only a limited effect on macrophage infection by the laboratory HIV-1, although infection by the primary isolates was markedly enhanced. We therefore conclude that the laboratory CXCR4-tropic HIV-1 isolate exhibits a significantly higher CXCR4 requirement for efficient infection than do the primary CXCR4-tropic isolates and that this difference can explain the poor ability of the laboratory HIV-1 isolate to replicate in primary macrophages. More generally, we propose that the cell tropisms displayed by different strains of HIV-1 in culture can largely be explained on the basis of differential requirements for cell surface CD4 and/or coreceptor expression levels.

* Corresponding author. Mailing address: Department of Genetics, Howard Hughes Medical Institute, Duke University Medical Center, Box 3025, Durham, NC 27710. Phone: (919) 684-3369. Fax: (919) 681-8979. E-mail: culle002{at}mc.duke.edu.

Journal of Virology, August 2001, p. 6776-6785, Vol. 75, No. 15
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.15.6776-6785.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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