SIV gp41 binds to membranes both in the monomeric and trimeric states: consequences for the neuropathology and inhibition of HIV infection.
The viral envelope glycoprotein gp41 mediates membrane fusion in HIV/SIV infection. gp41 ectodomain (e-gp41, residues 27-149), which was shown to interact with phospholipid membranes, exists in an equilibrium between the monomeric and trimeric states. Here, we analyzed, by intrinsic Trp fluorescence and resonance energy transfer, whether SIV e-gp41-membrane interaction depends on the gp41 oligomeric state. We found that both gp41 monomers and trimers bind membranes, with the monomers' full binding being reached at substantially lower lipid to protein ratios. Furthermore, the different characteristics of the Trp fluorescence of monomers and trimers enabled us to detect binding of each form at concentrations at which both species were present. CD spectroscopy revealed that the secondary structure of gp41 monomers does not change upon membrane binding, suggesting that membrane-bound monomeric-gp41 is a possible target for DP-178, a potent peptide inhibitor of HIV infection. The consequences of the interaction between monomeric and trimeric gp41 with membranes in HIV/SIV infection, its inhibition, and its associated neuropathologies are discussed.
Peisajovich
S G
SG
Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot, 76100, Israel.
Shai
Y
Y
D019380:Anti-HIV Agents / Q000378:metabolism / Q000494:pharmacology; D002942:Circular Dichroism; D004735:Energy Transfer; D000077560:Enfuvirtide; D005453:Fluorescence; D015700:HIV Envelope Protein gp41 / Q000378:metabolism / Q000494:pharmacology; D015658:HIV Infections / Q000378:metabolism / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology; D008081:Liposomes / Q000737:chemistry / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D010743:Phospholipids / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D012191:Retroviridae Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D015302:Simian Immunodeficiency Virus / Q000502:physiology
D019380:Anti-HIV Agents; D015700:HIV Envelope Protein gp41; D008081:Liposomes; D008562:Membrane Glycoproteins; D010446:Peptide Fragments; D010743:Phospholipids; D012191:Retroviridae Proteins; C082614:SIV envelope protein gp41; D000077560:Enfuvirtide