Epigallocatechin Gallate Inhibits Macaque SEVI-Mediated Enhancement of SIV or SHIV Infection

Abstract

Background Human semen contains a factor that can enhance HIV infection up to 10^5-fold in cultures. This factor is termed SEVI (Semen-derived Enhancer of Virus Infection), which is composed of proteolytic fragments (PAP248-286) from prostatic acid phosphatase (PAP) in semen. Here, we examined whether macaque SEVI can facilitate simian immunodeficiency virus (SIV) or chimeric simian/human immunodeficiency virus (SHIV) infection. We also studied the effect of EGCG on macaque SEVI-mediated SIV or SHIV enhancement. Methods SIV or SHIV was mixed with different concentrations of macaque SEVI in the presence or absence of epigallocatechin gallate (EGCG). The mixture was added to cultures of TZM-bl cells or macaque PBMC. The effect of EGCG on macaque SEVI was measured by Congo-red staining assay, thioflavin T (ThT) fluorescence assay and visualized by a transmission electron microscope. Results We identified that there is one amino acid difference at the site of 277 between human PAP248-286 and macaque PAP248-286. Macaque SEVI significantly enhanced SIV or SHIV infection of TZM-bl cells and macaque PBMC. EGCG could block macaque SEVI-mediated enhancement of SIV or SHIV infection. Mechanistically, EGCG could degrade the formation of macaque SEVI amyloid fibrils that facilitates HIV attachment to the target cells. Conclusions The finding that macaque SEVI could enhance SIV or SHIV infection indicates the possibility to use the macaque SEVI in vivo studies with the macaque models. In addition, future studies are necessary to examine whether EGCG can be used as an effective microbicide for preventing SIV or SHIV mucosal transmission.

Epigallocatechin-3-gallate local pre-exposure application prevents SHIV rectal infection of macaques

“…Furthermore, EGCG may confer an additional advantage over ARVs as it can counteract semen-mediated enhancement of HIV-1 infection. 23 , 29 We recently reported that EGCG counteracted macaque SEVI-mediated enhancement of SIV/SHIV infection of macaque PBMCs. 23 This finding is clinically relevant and important, as it has been reported that the anti-HIV-1 activity of a variety of potential microbicides could be compromised by the presence of semen or SEVI amyloid fibrils.…”

“… 23 , 29 We recently reported that EGCG counteracted macaque SEVI-mediated enhancement of SIV/SHIV infection of macaque PBMCs. 23 This finding is clinically relevant and important, as it has been reported that the anti-HIV-1 activity of a variety of potential microbicides could be compromised by the presence of semen or SEVI amyloid fibrils. 4 Therefore, in order to identify the best candidates for the prevention of HIV-1 sexual transmission, it is necessary to evaluate the anti-HIV-1 efficacy of the ARVs-formulated microbicides in the presence of semen.…”

“… 20 - 22 We recently reported that EGCG could also inhibit macaque SEVI (semen-derived enhancer of virus infection)-mediated enhancement of SIV/SHIV infection and degrade the formation of macaque semen-derived amyloid fibrils. 23 A most recent clinical study showed that EGCG is a well-tolerated and non-toxic therapeutic agent that can upregulate protective CC chemokines against HIV-1. 24 Taken together, these observations strongly argue for further studies, particularly in vivo investigations on the anti-HIV-1 effect of EGCG as an entry inhibitor.…”

From Ancient to Emerging Infections: The Odyssey of Viruses in the Male Genital Tract

“…The positive charges of the peptides interact with the negatively charged surfaces of cells and virions to form an electrostatic bridge that promotes viral attachment and fusion (29,578). Seminal plasma, SEVI, and semenogelin amyloids enhanced in vitro infection of isolated cells by HIV-1 (355,488), HIV-2 (355) SIV (775), HSV (690), CMV (673) and EBOV (42) but not that of ZIKV, WNV and DENV, which were inhibited by seminal plasma (487). SEVI also increased the internalization of EBOV particles by macropinocytosis, the canonical EBOV entry pathway, and stabilized EBOV viability and infectivity (42).…”

3-Hydroxyphthalic Anhydride- Modified Rabbit Anti-PAP IgG as a Potential Bifunctional HIV-1 Entry Inhibitor

“…Some compounds might be ideal SEVI antagonist-based microbicides by blocking the formation of SEVI or disassembling pre-formed SEVI fibrils. A natural ingredient of green tea, epigallocatechin-3-gallate (EGCG), seems to be an ideal antiretroviral agent by abrogating human and macaque SEVI-mediated enhancement of HIV-1 infection ( Popovych et al, 2012 ; Castellano et al, 2015b ; Zhou et al, 2017 ). An amyloid-remodeling nanomachine from yeast, Hsp104, antagonized semen-derived amyloid fibrils and reduced HIV transmission ( Castellano et al, 2015a ).…”