Helical conformation of the SEVI precursor peptide PAP248-286, a dramatic enhancer of HIV infectivity, promotes lipid aggregation and fusion.
In previous in vivo studies, amyloid fibers formed from a peptide ubiquitous in human seminal fluid (semen-derived enhancer of viral infection (SEVI)) were found to dramatically enhance the infectivity of the HIV virus (3-5 orders of magnitude by some measures). To complement those studies, we performed in vitro assays of PAP(248-286), the most active precursor to SEVI, and other polycationic polymers to investigate the physical mechanisms by which the PAP(248-286) promotes the interaction with lipid bilayers. At acidic (but not at neutral) pH, freshly dissolved PAP(248-286) catalyzes the formation of large lipid flocculates in a variety of membrane compositions, which may be linked to the promotion of convective transport in the vaginal environment rather than transport by a random Brownian motion. Furthermore, PAP(248-286) is itself fusiogenic and weakens the integrity of the membrane in such a way that may promote fusion by the HIV gp41 protein. An alpha-helical conformation of PAP(248-286), lying parallel to the membrane surface, is implicated in promoting bridging interactions between membranes by the screening of the electrostatic repulsion that occurs when two membranes are brought into close contact. This suggests that nonspecific binding of monomeric or small oligomeric forms of SEVI in a helical conformation to lipid membranes may be an additional mechanism by which SEVI enhances the infectivity of the HIV virus.
Brender
Jeffrey R
JR
Department of Chemistry, University of Michigan, Ann Arbor, Michigan, USA.
Hartman
Kevin
K
Gottler
Lindsey M
LM
Cavitt
Marchello E
ME
Youngstrom
Daniel W
DW
Ramamoorthy
Ayyalusamy
A
D000595:Amino Acid Sequence; D002384:Catalysis; D005260:Female; D006678:HIV / Q000737:chemistry; D015700:HIV Envelope Protein gp41 / Q000737:chemistry*; D015658:HIV Infections / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008051:Lipid Bilayers / Q000737:chemistry; D008055:Lipids / Q000737:chemistry; D008297:Male; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D012661:Semen / Q000821:virology*; D017386:Sequence Homology, Amino Acid; D014621:Vagina / Q000378:metabolism
D015700:HIV Envelope Protein gp41; D008051:Lipid Bilayers; D008055:Lipids; D010455:Peptides; D011108:Polymers