Semen‐derived amyloidogenic peptides—Key players of HIV infection

Abstract

Misfolding and amyloid aggregation of intrinsically disordered proteins (IDPs) are implicated in a variety of diseases. Studies have shown that membrane plays important roles on the formation of intermediate structures of IDPs that can initiate (and/or speed-up) amyloid aggregation to form fibers. The process of amyloid aggregation also disrupts membrane to cause cell death in amyloid diseases like Alzheimer's disease and type-2 diabetes. On the other hand, recent studies reported the membrane fusion properties of amyloid fibers. Remarkably, amyloid-fibril formation by short peptide fragments of highly abundant prostatic acidic-phosphatase (PAP) in human semen and are capable of boosting the rate of HIV infection up to 400,000-fold during sexual contact. Unlike the least toxic fully matured fibers of most amyloid proteins, the semen-derived enhancer of virus infection (SEVI) amyloid-fibrils of PAP peptide fragments are highly potent in rendering the maximum rate of HIV infection. This unusual property of amyloid fibers has witnessed increasing number of studies on the biophysical aspects of fiber formation and fiber-membrane interactions. NMR studies have reported a highly disordered partial helical structure in a membrane environment for the intrinsically disordered PAP peptide that promotes the fusion of the viral membrane with that of host cells. The purpose of this review article is to unify and integrate biophysical and immunological research reported in the previous studies on SEVI. Specifically, amyloid aggregation, dramatic HIV infection enhancing properties, membrane fusion properties, high resolution NMR structure, and approaches to eliminate the enhancement of HIV infection of SEVI peptides are discussed.

Mechanistic insights of host cell fusion of SARS-CoV-1 and SARS-CoV-2 from atomic resolution structure and membrane dynamics

“…Peptide fragments from abundant human semen protein prostatic acidic-phosphatase (PAP) or semen-derived enhancer of virus infection (SEVI) demonstrated enhanced infectivity, by a factor of 400,000-fold, of HIV [ 63 , 64 ]. Ramamoorthy and coworkers established a novel mechanism of PAP peptide fragment mediated enhancement of HIV infection [ [65] , [66] , [67] ]. The 39-residue long PAP 248 – 286 fragment forms amyloids like fibril structures which are efficient in membrane fusion and increased infectivity of HIV.…”

“…The 39-residue long PAP 248 – 286 fragment forms amyloids like fibril structures which are efficient in membrane fusion and increased infectivity of HIV. It has been proposed that SEVI amyloids bind to both the membranes of virion and host cells acting as a bridge towards efficient membrane fusion [ [65] , [66] , [67] ].…”

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“…The effect of PAP revolves around amyloid fibrils, which causes so-called semen-enhanced viral infection (SEVI). These SEVI capture HIV virions, thus, promoting their adhesion to target cells and increasing their ability to infect human cells, regardless of the cell type involved [ 43 , 44 , 45 ]. Reports specify that exposure of HIV particles to a concentration of 10% semen increases HIV infectivity up to 10-fold, and also shortens the exposure time to microbicides acting outside of the cell, which aim to avoid virus entry by impeding accessibility to virus membrane and glycoproteins [ 41 , 45 , 46 , 47 , 48 ].…”

The mechanism of phosphatidylcholine‐induced interference of PAP (248‐286) aggregation

“…1,2‐Dioleoyl‐ sn ‐glycero‐3‐phosphocholine (DOPC) represents one of the most common lipids that might have the ability to influence PAP 248‐286 structure . NMR spectroscopy intended to determine the high‐resolution structure of the peptide in aqueous solution, and membrane environment suggested that this peptide is a highly disordered system . Adoption of disordered structure upon binding with membrane makes PAP 248‐286 remarkably different than other existing amyloidogenic peptides because most of them acquire α‐helical structures in membrane environment .…”