Several CD4 domains can play a role in human immunodeficiency virus infection in cells

Abstract

The human immunodeficiency virus (HIV) uses the human CD4 glycoprotein as a receptor for infection of susceptible cells. Cells expressing a series of mutated forms of the CD4 gene have shown a variability in their ability to support replication of three HIV type 1 (HIV-1) and three HIV-2 strains. Moreover, when different stages of virus production were examined by a variety of assays, a consistent delay was observed in all cell lines containing CD4 mutants compared with those with intact full-length CD4. Ceils expressing the CD4.415 mutant (modffied at the serine 415 corresponding to a phosphorylation site of the cytoplasmic domain) showed only a minimal effect on virus replication. Cells expressing CD4.403 and CD4.401 mutants (lacking the whole cytoplasmic domain) manifested a moderate delay in production of virus progeny. The most substantial effect on HIV replication was observed in cells expressing a chimeric hybrid containing sequences corresponding to the first 177 residues of the N-terminal CD4 fused to CD8 sequences encoding the hinge, transmembrane, and cytoplasmic domains of the human CD8. Furthermore, in a cell-to-cell contact assay, fusion was absent when the CD4 proximal membrane domain was replaced by the CD8 counterpart. In addition, a strong correlation between the down-modulation of the surface CD4 and HIV expression was observed. These observations suggest that in addition to the known binding region, other domains of CD4 could play an important role in regulating HIV entry of cells.

Specific CD4 down-modulating compounds with potent anti-HIV activity

“…Thus, a CD4-lowering drug could inhibit viral infection by not only blocking viral entry, but also making the virus more prone to elimination by the neutralizing action of antibodies. Furthermore, as several domains of CD4 play an important role in regulating HIV entry of cells [73], a specific down-modulator of the complete CD4 receptor may be considered as a more effective antiviral agent.…”

Cell entry by measles virus: long hybrid receptors uncouple binding from membrane fusion

“…Distance effects might influence membrane fusion during cell entry of other viruses. Transferring the HIV binding site nearer to the cell membrane resulted in loss of fusion (35); however, this study was designed to define the CD4 domains which play a role in HIV entry and not to study a distance effect. It was also recently observed that retroviruses expressing a foreign epitope on their envelope specifically bound a new surface receptor but that infection was blocked at a postbinding step (10).…”

Role of CD4 epitopes outside the gp120-binding site during entry of human immunodeficiency virus type 1

“…The graph shows the mean fluorescence channels for duplicate determinations with standard errors. 41). The MAbs against D3D4 of rat CD4 can be placed in distinct functional groups as a result of our experiments.…”