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Myricetin Antagonizes Semen-Derived Enhancer of Viral Infection (SEVI

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Myricetin Antagonizes Semen-Derived Enhancer of Viral Infection (SEVI Ren et al. Retrovirology (2018) 15:49 https://doi.org/10.1186/s12977-018-0432-3 Retrovirology RESEARCH Open Access Myricetin antagonizes semen‑derived enhancer of viral infection (SEVI) formation and infuences its infection‑enhancing activity Ruxia Ren1,2†, Shuwen Yin1†, Baolong Lai2, Lingzhen Ma1, Jiayong Wen1, Xuanxuan Zhang1, Fangyuan Lai1, Shuwen Liu1* and Lin Li1* Abstract Background: Semen is a critical vector for human immunodefciency virus (HIV) sexual transmission and harbors seminal amyloid fbrils that can markedly enhance HIV infection. Semen-derived enhancer of viral infection (SEVI) is one of the best-characterized seminal amyloid fbrils. Due to their highly cationic properties, SEVI fbrils can capture HIV virions, increase viral attachment to target cells, and augment viral fusion. Some studies have reported that myri- cetin antagonizes amyloid β-protein (Aβ) formation; myricetin also displays strong anti-HIV activity in vitro. Results: Here, we report that myricetin inhibits the formation of SEVI fbrils by binding to the amyloidogenic region of the SEVI precursor peptide (PAP248–286) and disrupting PAP248–286 oligomerization. In addition, myricetin was found to remodel preformed SEVI fbrils and to infuence the activity of SEVI in promoting HIV-1 infection. Moreover, myricetin showed synergistic efects against HIV-1 infection in combination with other antiretroviral drugs in semen. Conclusions: Incorporation of myricetin into a combination bifunctional microbicide with both anti-SEVI and anti- HIV activities is a highly promising approach to preventing sexual transmission of HIV. Keywords: HIV, Myricetin, Amyloid fbrils, SEVI, Synergistic antiviral efects Background in vivo because they facilitate virus attachment and inter- Since the frst cases of acquired immune defciency nalization into cells [4]. A naturally occurring C-proximal syndrome (AIDS) were reported in 1981, more than 70 proteolytic fragment of prostatic acid phosphatase (PAP) million people have been infected by human immuno- in semen, PAP248–286, has been reported to form aggre- defciency virus (HIV), and approximately 1 million die gated amyloid fbrils (known as semen-derived enhancer of the disease annually [1]. Currently, unprotected sex of virus infection or SEVI) and to increase by several remains the major route of HIV transmission, accounting orders of magnitude the rate of HIV infection in vitro [5]. for more than 80% of new HIV infections worldwide [2]. Because SEVI is highly cationic and the fbrils it forms It has been shown that semen functions as a critical are positively charged, it not only efectively captures carrier of virus during sexual transmission [3]. Notably, HIV virions but also promotes viral attachment to target amyloid fbrils in semen are considered to be responsible cells by neutralizing the inherent electrostatic repulsion for the reduced efcacy of antiretroviral therapies (cART) between the negative charges on the surfaces of the viri- ons and target cells [6]. Some other endogenous amyloid *Correspondence: [email protected]; [email protected] aggregates that increase HIV-1 infectivity, including the †Ruxia Ren and Shuwen Yin contributed equally to this work PAP N-proximal fragment (PAP85–120) and semenoge- 1 Guangdong Provincial Key Laboratory of New Drug Screening, Guangzhou Key Laboratory of Drug Research for Emerging Virus lins (SEM1 and SEM2), have been identifed in human Prevention and Treatment, School of Pharmaceutical Sciences, Southern semen [7, 8], which may explain the discrepancy between Medical University, 1838 Guangzhou Avenue North, Guangzhou 510515, the low infectiousness of HIV in vitro and its observed Guangdong, China Full list of author information is available at the end of the article efcient sexual transmission. © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat​iveco​mmons​.org/licen​ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat​iveco​mmons​.org/ publi​cdoma​in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Ren et al. Retrovirology (2018) 15:49 Page 2 of 24 As amyloid species that are naturally abundant Results in semen, including SEVI, play a critical role in the Myricetin inhibits the formation of SEVI fbrils and other spread of HIV, they represent a particularly attrac- seminal fbrils tive target for the development of molecules that can Tiofavin T (TT), a dye that is commonly used in the reduce spread of the virus. Theoretically, eliminating detection of amyloid fbrils, can intercalate into the seminal amyloid fibrils by antagonizing fibril forma- β-sheet structure of amyloid fbrils, resulting in enhanced tion or enhancing the degradation of mature endog- fuorescence and a characteristic redshift in the emis- enous fibrils can massively reduce any viral infection sion spectrum. Congo red, another amyloid-binding dye, enhancement [9–11]. This strategy might be advanta- exhibits apple-green birefringence under polarized light geous because it targets host factors rather than the as well as increased fuorescence [7, 24]. To evaluate virus itself. the efects of myricetin on the formation of SEVI fbrils It is well known that the aggregation of proteins into by PAP248–286, we collected PAP248–286 aggregates amyloid fibrils is associated with fatal diseases, includ- formed in the presence or absence of various concentra- ing Alzheimer’s disease, Parkinson’s disease and dia- tions of myricetin at diferent time points and monitored betes, and many molecules that inhibit fibrillization them using both TT fuorescence and Congo red stain- in vitro have been reported. For instance, epigallocat- ing assays. Te results showed that myricetin antago- echin-3-gallate (EGCG), the major catechin present in nized the assembly of PAP248–286 monomers into SEVI green tea, not only potently inhibits the amyloidogene- fbrils in a dose-dependent manner. Te addition of myri- sis of various polypeptides but is also able to disassem- cetin at 75 µg/ml increased the lag time of SEVI amyloid ble a wide range of preformed amyloid fibrils [12, 13]. fbril formation by PAP248–286 to more than 48 h, as Myricetin, a common dietary flavonoid found in measured by TT fuorescence (Fig. 1a), whereas the lag foods such as walnuts, onions, berries, herbs and time of amyloid fbril formation by PAP248–286 in the red grapes, exerts a wide variety of biological and absence of myricetin was less than 6 h. Congo red assays nutraceutical effects, including antioxidative, anti- showed that the lag time of SEVI amyloid fbril formation inflammatory, antidiabetic, antitumor and free radi- in the presence of various concentrations of myricetin cal-scavenging activities [14–16]. Moreover, myricetin was extended to approximately 18 h (Fig. 1b). Te mor- shows activity against HIV-1 infection by inhibiting phology of SEVI fbrils in the presence and absence of HIV-1 integrase [17, 18]. It is noteworthy that myri- myricetin was imaged by transmission electron micros- cetin inhibits amyloid fibrillization by a variety of copy (TEM). As shown in Fig. 1c, mature SEVI fbrils disease-associated amyloidogenic proteins, includ- formed by PAP248–286 were identifed after shaking for ing amyloid β-protein (Aβ), tau protein, islet amy- 24 h, whereas no amyloid fbrils were observed after add- loid polypeptide and other amyloidogenic peptides ing 16 μg/ml of myricetin, even after shaking for 48 h. [19–21]. As described above, SEVI is a possible drug Far-UV (190–260 nm) circular dichroism (CD) spec- target for preventing HIV sexual transmission due to trum measurement is commonly used to detect the its stable structure and high levels in semen [22]. The presence of the typical secondary β-sheet structure of concentration of endogenous SEVI in pooled semen is fbrils; such fbrils display a spectrum with a minimum approximately 35 µg/ml, which considerably exceeds at approximately 218 nm. A characteristic β-sheet sec- the level (≥ 2 µg/ml) required to enhance infection ondary structure undergoes higher-level association to [7, 23]. However, it is not known whether myricetin form protein aggregates and mature fbrils. Tus, we fur- affects the formation of SEVI amyloid fibrils in semen. ther investigated the secondary structure of SEVI fbrils In the current study, we sought to elucidate the effects formed in the presence or absence of myricetin by meas- of myricetin on the formation of SEVI amyloid fibrils uring their CD spectra. As illustrated in Fig. 1e, the spec- and on the enhancement of HIV-1 infection by SEVI. trum of PAP248–286 after agitation for 24 h displayed Strikingly, the results showed that myricetin influences a single minimum at approximately 230 nm, indicating the activity of SEVI in enhancing HIV-1 infection and the presence of a typical β-sheet component. However, that it exhibits synergistic effects in semen against the spectrum of PAP248–286 after agitation for 24 h in HIV-1 infection when applied to cells in combination the presence of 5 μg/ml myricetin (fnal concentration) with other antiretroviral (ARV) agents. These findings indicated the presence of a characteristic random coil will be helpful in the development of dual-function structure, suggesting that PAP248–286 did not adopt antiviral drugs or microbicides that possess both anti- any ordered or stable conformation and indicating that HIV and anti-SEVI-enhancing activities. β-sheet aggregation had not occurred. Ren et al. Retrovirology (2018) 15:49 Page 3 of 24 Fig. 1 Myricetin inhibits the assembly of PAP248–286. PAP248–286 (3 mg/ml) was incubated with myricetin (75, 37.5, 18.75, 9.375 and 0 μg/ml), and the mixture was agitated at 1400 rpm at 37 °C. Samples were collected at various time points (0, 6, 12, 18, 24 and 48 h) and monitored by ThT (a) or Congo red staining (b).
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