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Papers In Press, published online ahead of print November 9, 2001
Department of Medicine, University of California, San Diego, La Jolla, CA 92093-0665
Corresponding Author: jlama{at}ucsd.edu
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 (PBLs) 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 (VSVg) 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 downmodulate the viral receptor in infected cells. Our findings have important implications for the spread of HIV in vivo and suggest that the CD4 downmodulation function may be an alternative target for therapeutic intervention
J. Biol. Chem, 10.1074/jbc.M109807200
Submitted on October 10, 2001
Revised on November 7, 2001
Accepted on November 8, 2001
Cell-surface CD4 interferes with the infectivity of HIV-1 particles released from T cells
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