An α-Helical Conformation of the SEVI Peptide, a Dramatic Enhancer of HIV Infectivity, Promotes Lipid Aggregation and Fusion

Abstract

A peptide ubiquitous in human seminal fluid has been recently described that dramatically enhances the infectivity of the HIV virus (3-5 orders of magnitude by some measures). Previous studies have shown that this peptide, a fragment of human Prostatic Acid Phosphatase (PAP248-286) referred to as SEVI (Semen-derived Enhancer of Viral Infection), is amyloidogenic and the enhancement of viral infectivity is dependent on the aggregation state of the peptide. To complement these previous in vivo studies we have performed in vitro assays to investigate the physical mechanisms by which the PAP248-286 promotes the interaction with lipid bilayers. Our results indicate a strong interaction of freshly dissolved PAP248-286 with lipid bilayers but a weaker interaction with the amyloid form of PAP248-286, as measured by the tendency of freshly dissolved PAP248-286 to induce aggregation of lipid vesicles and membrane fusion. The amyloid form of PAP248-286 had little effect on either vesicle aggregation or fusion. To further investigate this effect we have solved the structure of PAP248-286 in SDS micelles. A largely α-helical conformation of PAP248-286, 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 non-specific binding of small oligomeric forms of SEVI in an α-helical conformation to lipid membranes may be an additional mechanism by which SEVI enhances the infectivity of the HIV virus.