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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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