Possible role of nonprotein components of the plasma membrane in CD4-dependent membrane fusion and HIV entry

Summary

In most situations, HIV enters a cell by a membrane fusion process mediated by its envelope proteins (Env, gp120/gp41), which is triggered by the interaction of gp120 with CD4. Membrane fusion and virus entry probably require other human-specific molecule(s) (often designated as ‘fusion cofactors’), since: (i) CD4⁺ cells of nonhuman origin are resistant to HIV entry and Env-mediated fusion; and (ii) heterokaryons formed between nonhuman CD4⁺ cells and human CD4⁻ cells are permissive to these processes. Most types of human cells, including red blood cells (RBC), were found to complement murine cells and must therefore express the fusion cofactors. The complementation efficiency was not reduced if RBC membranes (ghosts) were used instead of intact RBC, or if RBC were extensively digested with proteinase K or pronase. These experiments confirm that the fusion cofactors are associated to the plasma membrane, and raise the possibility they could be nonprotein components, in particular complex lipids. Among these, glycosphingolipids (GSL) seem to have a diversity consistent with the existence of human-specific types. This hypothesis could explain why CD4⁺ cells could not be rendered permissive to HIV entry by transfection of human DNA, or by forming stable hybrid cell lines bearing human chromosomes. Until now, attempts to complement CD4⁺ murine cells by transferring GSL-enriched lipidic fractions prepared from human cells have not been successful. Also, treatments with enzymes or metabolic inhibitors aimed at reducing GSL expression did not seem to alter the permissivity of CD4⁺ human cells. However, these experiments have a number of technical limitations, and in spite of these negative results, the role of complex lipids in HIV entry deserves further investigation.