Seminal Plasma Accelerates Semen-derived Enhancer of Viral Infection (SEVI) Fibril Formation by the Prostatic Acid Phosphatase (PAP248–286) Peptide

Abstract

<jats:p>Amyloid fibrils contained in semen, known as SEVI, or semen-derived enhancer of viral infection, have been shown to increase the infectivity of HIV dramatically. However, previous work with these fibrils has suggested that extensive time and nonphysiologic levels of agitation are necessary to induce amyloid formation from the precursor peptide (a proteolytic cleavage product of prostatic acid phosphatase, PAP<jats:sub>248–286</jats:sub>). Here, we show that fibril formation by PAP<jats:sub>248–286</jats:sub>is accelerated dramatically in the presence of seminal plasma (SP) and that agitation is not required for fibrillization in this setting. Analysis of the effects of specific SP components on fibril formation by PAP<jats:sub>248–286</jats:sub>revealed that this effect is primarily due to the anionic buffer components of SP (notably inorganic phosphate and sodium bicarbonate). Divalent cations present in SP had little effect on the kinetics of fibril formation, but physiologic levels of Zn<jats:sup>2+</jats:sup>strongly protected SEVI fibrils from degradation by seminal proteases. Taken together, these data suggest that in the<jats:italic>in vivo</jats:italic>environment, PAP<jats:sub>248–286</jats:sub>is likely to form fibrils efficiently, thus providing an explanation for the presence of SEVI in human semen.</jats:p>

Repurposing Hsp104 to Antagonize Seminal Amyloid and Counter HIV Infection

“…Naturally occurring fragments of proteins abundant in semen form amyloid fibrils (Usmani et al, 2014), and the unique composition of semen drives the fibrillization process (Olsen et al, 2012). Specifically, proteolytic fragments of prostatic acid phosphatase (PAP248-286 (SEVI) and PAP85-120), semenogelin 1 (SEM1), and semenogelin 2 (SEM2) form fibrils that enhance HIV infectivity by several orders of magnitude under conditions of limiting viral inoculum, whereas the soluble, non-amyloid peptides have no effect (Arnold et al, 2012; Munch et al, 2007; Roan et al, 2011).…”

ADS-J1 Inhibits Semen-Derived Amyloid Fibril Formation and Blocks Fibril-Mediated Enhancement of HIV-1 Infection

“…Therefore, the dual functions of ADS-J1 of inhibiting semen-derived amyloid fibrils and blocking HIV-1 entry make it a plausible candidate for incorporation into combination microbicide formulations. ADS-J1 might readily bind to amyloidogenic peptide to inhibit seminal fibril formation, which might be a spontaneous process under physiologic conditions (34), and it also might target mature fibrils to prevent the augmented viral infection (Fig. 1E).…”

Misfolding of Amyloidogenic Proteins and Their Interactions with Membranes

“…The hypothesis of amyloid as a generic protein fold has been reinforced by the discovery of a number of amyloid structures associated with normal physiologic conditions, not only in simple organisms such as bacteria, fungi or insects but also in humans [2,3,4]. We will focus on pathological amyloid, although structures and assembly of all amyloids have similarities.…”