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J. Biol. Chem., Vol. 277, Issue 3, 1770-1779, January 18, 2002
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From the Departments of The CD4 protein is required for the entry of
human immunodeficiency virus (HIV) into target cells. Upon expression
of the viral genome, three HIV-1 gene products participate in the
removal of the primary viral receptor from the cell surface. To
investigate the role of surface-CD4 in HIV replication, we have created
a set of Jurkat cell lines which constitutively express surface levels
of CD4 comparable to those found in peripheral blood lymphocytes and monocytes. Expression of low levels of CD4 on the surface of
producer cells exerted an inhibitory effect on the infectivity of HIV-1
particles, whereas no differences in the amount of cell-free p24
antigen were observed. Higher levels of cell surface CD4 exerted a
stronger inhibitory effect on infectivity, and also affected the
release of free virus in experiments where the viral genomes were
delivered by electrotransfection. The CD4-mediated inhibition of HIV-1
infectivity was not observed in experiments where the vesicular
stomatitis virus G protein was used to pseudotype viruses, suggesting
that an interaction between CD4 and gp120 is required for interference.
In contrast, inhibition of particle release by high levels of
cell-surface CD4 was not overcome by pseudotyping HIV-1 with foreign
envelope proteins. Protein analysis of viral particles released from
HIV-infected Jurkat-T cells revealed a CD4-dependent
reduction in the incorporation of gp120. These results demonstrate that
physiological levels of cell-surface CD4 interfere with HIV-1
replication in T cells by a mechanism that inhibits envelope
incorporation into viral membranes, and therefore provide an
explanation for the need to down-modulate the viral receptor in
infected cells. Our findings have important implications for the spread
of HIV in vivo and suggest that the CD4 down-modulation function may be an alternative target for therapeutic intervention.
Cell Surface CD4 Interferes with the Infectivity of HIV-1
Particles Released from T Cells*
,§, and¶
Medicine and
§ Biology, University of California, San Diego,
La Jolla, California 92093-0665
*
This work was supported by the Center for AIDS Research at
the University of California, San Diego, National Institutes of Health
program Grant P30AI36214-905, the University of California Universitywide AIDS research program Grant R99-SD-58A, The Campbell Foundation, and the United States Public Health Service, National Institutes of Health Grant DA13866-01 (to J. L.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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