Targeting anti-HIV-I peptide T20 to membrane raft domains may not improve proposed gene-therapeutic strategy
Krefman, Nathaniel I.
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HIV -1 fusion with CD4-expressing host cells requires a sequence of interactions between lipid raft-associated host cell-surface receptor proteins (CD4 and either CCR5 or CXCR4) and viral envelope proteins (gp120 and gp41). Lipid rafts, which are liquid-ordered cell membrane units that exhibit relatively high lateral mobility in the mostly liquid-disordered membrane, are recruited to the viral entry site during an early stage of the fusion process. Several anti-HIV-1 peptides have been derived from gp41 and inhibit fusion. Anchoring such peptides in rafts might exploit this recruitment event. One particular peptide, T20, is in a new class of HIV -1 drugs called the fusion inhibitors. The sequence of T20 is derived from a region of gp41 that participates in an intra-protein interaction after the gp41 fusion peptide anchors the virus to the target cell. This crucial interaction folds the protein into a conformation that is thought to bring the viral envelope and plasma membrane together and produce the free-energy change necessary to make the membranes contiguous and ultimately form a fusion pore. T20 competitively obstructs interaction between the two regions, precluding fusion. Publications reporting that a membrane-expressed gp41-derived peptide inhibits fusion in vitro led our lab to examine the expression of T20 in raft domains of 293CD4+ cells, in pursuit of a sophisticated gene therapeutic strategy for HIV -1. Assays of cell-cell fusion, however, revealed that expression of raft-anchored T20 increased, rather than decreased, fusion. If replicated, though, this finding could potentially open a debate concerning the commonly accepted view of the mechanism by which T20 inhibits fusion.