Clues for the Mechanism of SEVI HIV Enhancement from Structural Studies of the SEVI Precursor Peptide PAP248-286 in a Membrane Environment by NMR

Abstract

Despite the rapid progress of the AIDS pandemic, the HIV virus is a surprisingly weak pathogen in vitro. The large difference between in vitro and in vivo infection rates suggests that cofactors absent in vitro but essential for the natural transmission of the virus may be responsible for this discrepancy. A recently identified peptide in human semen, PAP248-286, has emerged as a clear candidate for the missing cofactor as it dramatically enhances the infectivity of HIV by up to five orders of magnitude. PAP248-286 appears to enhance HIV infection by forming amyloid fibers known as SEVI, which are believed to enhance the attachment of the virus by bridging interactions between virion and host-cell membranes. To understand the unique ability of SEVI to enhance HIV infection, we have solved the atomic-level resolution structure of the SEVI precursor PAP248-286 using NMR spectroscopy in SDS micelles. In contrast to other toxic amyloid peptides that generally penetrate into the core of the membrane, non-toxic PAP248-286 binds superficially to the surface of the micelle. Unlike most amyloid peptides that bind to the membrane in an α-helical state, PAP248-286 is mostly disordered when bound to the surface of the micelle. The highly disordered nature of the SEVI peptide may explain the high ability of SEVI to enhance HIV infection, as partially disordered amyloid fibers will have a greater capture radius for the virus than more compact amyloid fibers. Two regions of nascent structure match the prediction of highly amyloidogenic sequences and may serve as nuclei for aggregation and amyloid fibril formation. NMR studies of the binding of PAP248-286 to the anti-amyloid agent ECGC will also be presented.