Human immunodeficiency virus 1 gp41 folds into a six-helix bundle whereby three C-terminal heptad repeat regions pack in an antiparallel manner against the coiled-coil formed by three N-terminal heptad repeats (NHR). Peptides that inhibit bundle formation contributed significantly to the understanding of the entry mechanism of the virus. DP178, which partially overlaps C-terminal heptad repeats, prevents bundle formation through an undefined mechanism; additionally it has been suggested to bind other ENV regions and arrest fusion in an unknown manner. We used two structurally altered DP178 peptides; in each, two sequential amino acids were substituted into their D configuration, D-SQ in the hydrophilic N-terminal region and D-LW in the hydrophobic C-terminal. Importantly, we generated an elongated NHR peptide, N54, obtaining the full N-helix docking site for DP178. Interestingly, D-LW retained wild type fusion inhibitory activity, whereas D-SQ exhibited significantly reduced activity. In correlation with the inhibitory data, CD spectroscopy and fluorescence studies revealed that all the DP178 peptides interact with N54, albeit with different stabilities of the bundles. We conclude that strong binding of DP178 N-terminal region to the endogenous NHR, without significant contribution of the C-terminal sequence of DP178 to core formation, is vital for DP178 inhibition. The finding that D-amino acid incorporation in the C terminus did not affect activity or membrane binding as revealed by surface plasmon resonance correlates with an additional membrane binding site, or membrane anchoring role, for the C terminus, which works synergistically with the N terminus to inhibit fusion. HIV-12 utilizes a glycoprotein embedded in its outer membrane for entering its target cell. One of its subunits, gp41, enables the actual fusion action (reviewed in Refs. 1 and 2) and contains several functional regions: N-terminal fusion peptide, N-terminal heptad repeat (NHR), C-terminal heptad repeat (CHR), and the pre-transmembrane region (Fig. 1). gp41 possesses at least three major conformational states during the fusion process: (i) a native metastable conformation in the intact virion in which gp41 is sheltered by gp120 (3, 4); (ii) the pre-hairpin conformation following receptor binding in which three NHR regions create a coiled-coil, positioning the fusion peptide close to the host membrane (5, 6); and (iii) the hairpin conformation preceding pore formation in which the six-helix bundle is formed whereby three CHR regions pack in an anti-parallel manner into hydrophobic grooves created by the central coiled-coil (7,8). Peptides derived from the NHR and CHR regions of gp41 are known to inhibit HIV-1 fusion (4, 9). It is believed that these fusion inhibitors bind their endogenous counterparts, blocking the progression from pre-hairpin to hairpin conformation, thereby arresting the fusion process. One of these peptides, DP178 (10), was recently approved by the Food and Drug Administration and is currently part of HIV-1 treatment.The e...
HIV-1 infects host cells by sequential interactions of its fusion protein (gp120-gp41) with receptors CD4, CXCR4 and/or CCR5 followed by fusion of viral and host membranes. Studies indicate that additional factors such as receptor density and composition of viral and cellular lipids can dramatically modulate the fusion reaction. Lipid rafts, which primarily consist of sphingolipids and cholesterol, have been implicated for infectious route of HIV-1 entry. Plasma membrane Glycosphingolipids (GSLs) have been proposed to support HIV-1 infection in multiple ways: (a) as alternate receptor(s) for CD4-independent entry in neuronal and other cell types, (b) viral transmission, and (c) gp120-gp41-mediated membrane fusion. However, the exact mechanism(s) by which GSLs support fusion is still elusive. This article will focus on the contribution of target membrane sphingolipids and their metabolites in modulating viral entry. We will discuss the current working hypotheses underlying the mechanisms by which these lipids promote and/or block HIV-1 entry. Recent approaches in the design and development of novel glycosyl derivatives, as anti-HIV agents will be summarized.
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