Direct visualization of HIV-enhancing endogenous amyloid fibrils in human semen

Abstract

Naturally occurring fragments of the abundant semen proteins prostatic acid phosphatase (PAP) and semenogelins form amyloid fibrils in vitro. These fibrils boost HIV infection and may play a key role in the spread of the AIDS pandemic. However, the presence of amyloid fibrils in semen remained to be demonstrated. Here, we use state of the art confocal and electron microscopy techniques for direct imaging of amyloid fibrils in human ejaculates. We detect amyloid aggregates in all semen samples and find that they partially consist of PAP fragments, interact with HIV particles and increase viral infectivity. Our results establish semen as a body fluid that naturally contains amyloid fibrils that are exploited by HIV to promote its sexual transmission.

Structure-Based Design of Functional Amyloid Materials

“…23 The underlying mechanism has been postulated to involve electrostatic attraction: the positively charged fibers mediate the interaction between negatively charged viral and cellular membranes, thus suggesting the possibility of enhancing retroviral transduction in basic research and clinical applications. 23,45,46 According to this postulated mechanism, we incorporated various numbers of lysines in the peptides ( Table 2). Given that arginine has a higher pK a than lysine, we also incorporate arginine in some designs.…”

Amyloid fibril proteins and amyloidosis: chemical identification and clinical classification International Society of Amyloidosis 2016 Nomenclature Guidelines

“…Fibrillar fragments of prostatic acidic phosphatase (PAP) have been termed Semen-derived Enhancer of Virus Infection [12] and have been shown to form in vivo [13], although their role in transmission has been recently questioned [14].…”

Gallic Acid Is an Antagonist of Semen Amyloid Fibrils That Enhance HIV-1 Infection

“…Amyloid fibrils are also found in semen from young, healthy men (4). Whether these fibrils serve a physiological function is not known, but they have been shown to markedly increase infection by a variety of sexually transmitted viruses, most notably HIV-1 (5-7).…”

“…They are characterized by their cross-␤ structure, with ␤ sheets running perpendicular to the fibril axis, and by their ability to bind to certain fluorescent dyes, such as thioflavin T (ThT), 4 whose fluorescence intensity increases considerably upon binding to amyloid fibrils.…”

“…□ S This article contains supplemental Fig. 1 4 The abbreviations used are: ThT, thioflavin T 4-(3,6-dimethyl-1,3-benzothiazol-3-ium-2-yl)-N,N-dimethylaniline chloride (an amyloid-specific dye); PAPf39, a 39-residue fragment (residues 248 -286) of human prostatic acid phosphatase; SEVI, semen-derived enhancer of viral infection (semen fibril made up of PAPf39 peptide); Congo Red, 4-amino-3-[4-[4-(1-amino-4-sulfonato-naphthalen-2-yl)diazenylphenyl]phenyl]diazenyl-naphthalene-1-sulfonate (an amyloid specific dye); SEM1 fibrils, semen fibrils made up of a 22-residue fragment (residues 86 -107) of human semenogelin 1; AFM, atomic force microscopy; PB, sodium phosphate buffer, pH 7.4; SP, seminal plasma. …”