Semen-mediated enhancement of HIV infection is donor-dependent and correlates with the levels of SEVI

Institute of Molecular Virology, University Hospital Ulm, 89081 Ulm, Germany.
Retrovirology (Impact Factor: 4.19). 06/2010; 7(1):55. DOI: 10.1186/1742-4690-7-55
Source: PubMed

ABSTRACT HIV-1 is usually transmitted in the presence of semen. We have shown that semen boosts HIV-1 infection and contains fragments of prostatic acid phosphatase (PAP) forming amyloid aggregates termed SEVI (semen-derived enhancer of viral infection) that promote virion attachment to target cells. Despite its importance for the global spread of HIV-1, however, the effect of semen on virus infection is controversial.
Here, we established methods allowing the meaningful analysis of semen by minimizing its cytotoxic effects and partly recapitulating the conditions encountered during sexual HIV-1 transmission. We show that semen rapidly and effectively enhances the infectivity of HIV-1, HIV-2, and SIV. This enhancement occurs independently of the viral genotype and coreceptor tropism as well as the virus producer and target cell type. Semen-mediated enhancement of HIV-1 infection was also observed under acidic pH conditions and in the presence of vaginal fluid. We further show that the potency of semen in boosting HIV-1 infection is donor dependent and correlates with the levels of SEVI.
Our results show that semen strongly enhances the infectivity of HIV-1 and other primate lentiviruses and that SEVI contributes to this effect. Thus, SEVI may play an important role in the sexual transmission of HIV-1 and addition of SEVI inhibitors to microbicides may improve their efficacy.

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    • "We found that SP and SEVI enhanced infection by both HIV-1 and SIVmac, although the effects on the latter were substantially weaker (Figure 1A and B). SP was most effective at 10% (Figure 1A) since 50% begins to cause cytotoxic effects [10,13]. In contrast, the enhancing effect of SEVI did not saturate (Figure 1B). "
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    ABSTRACT: Semen and semen-derived amyloid fibrils boost HIV infection in vitro but their impact on sexual virus transmission in vivo is unknown. Here, we examined the effect of seminal plasma (SP) and semen-derived enhancer of virus infection (SEVI) on vaginal virus transmission in the SIV/rhesus macaque (Macacca mulatta) model. A total of 18 non-synchronized female rhesus macaques (six per group) were exposed intra-vaginally to increasing doses of the pathogenic SIVmac239 molecular clone in the presence or absence of SEVI and SP. Establishment of productive virus infection was assessed by measuring plasma viral RNA loads at weekly intervals. We found that the first infections occurred at lower viral doses in the presence of SP and SEVI compared to the control group. Furthermore, the average peak viral loads during acute infection were about 6-fold higher after exposure to SP- and SEVI-treated virus. Overall infection rates after a total of 27 intra-vaginal exposures to increasing doses of SIV, however, were similar in the absence (4 of 6 animals) and presence of SP (5 of 6), or SEVI (4 of 6). Furthermore, the infectious viral doses required for infection varied considerably and did not differ significantly between these three groups. Semen and SEVI did not have drastic effects on vaginal SIV transmission in the present experimental setting but may facilitate spreading of virus infection after exposure to low viral doses that most closely approximate the in vivo situation.
    Retrovirology 12/2013; 10(1):148. DOI:10.1186/1742-4690-10-148 · 4.19 Impact Factor
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    • "Prostatic acid phosphatase (~50 kDa) is a glycosylated enzyme secreted by the prostatic epithelium and functions in semen liquefaction (Ortlund et al., 2003). PAP is also proposed to play a role in enhanced human immunodeficiency virus (HIV) infectivity by forming amyloid aggregates called semen-derived enhancer of viral infection that promote virion attachment to target cells (Kim et al., 2010). Therefore, in prostasomes, galectin-3 and PAP may be involved in the transfer of HIV to the female reproductive tract. "
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    ABSTRACT: Galectin-3 is a multifunctional carbohydrate-binding protein that was previously characterized as a proteolytic substrate for prostate-specific antigen (PSA) and was shown to be associated with prostasomes in human semen. Prostasomes are exosome-like vesicles that are secreted by the prostatic epithelium and have multiple proposed functions in normal reproduction and prostate cancer. In the current study, galectin-3 binding ligands in human prostasomes were identified and characterized with the goal to investigate galectin-3 function in prostasomes. Galectin-3 binding proteins were isolated by affinity column chromatography. Candidate ligands identified by MS/MS were PSA, prostatic acid phosphatase (PAP), zinc alpha-2-glycoprotein (ZAG), dipeptidyl peptidase-4 (CD26), aminopeptidase N (CD13), neprilysin, clusterin, antibacterial protein (FALL-39) and alpha-1-acid glycoprotein (ORM1). Biochemical methods were used to characterize the ability of galectin-3 to bind to selected ligands, and galectin-3 cleavage assays were utilized to investigate the protease(s) in prostasomes that cleaves galectin-3. CD26, CD13, PSA, PAP and ZAG immunoreactivity were detected in extracts of purified prostasomes. One-dimensional electroblot analysis of prostasomes demonstrated that CD26, PAP and CD13 immunoreactivity co-migrated with galectin-3-reactive protein bands. PSA and ZAG were found to be associated with the surface of prostasomes. Both intact and cleaved galectin-3 were detected in prostate and prostasome extracts. Cleavage and inhibition assays indicated that PSA in prostasomes proteolytically cleaves galectin-3. The identification of these glycoproteins as galectin-3 ligands lays the groundwork for future studies of galectin-3 and prostasome function in reproduction and prostate cancer.
    Andrology 07/2013; 1(5). DOI:10.1111/j.2047-2927.2013.00099.x · 2.30 Impact Factor
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    • "At the same time, these polyanions could also aggravate SE-F induced enhancement of X4 tropic HIV-1 infections (Fig. 8B). As a result of donor-to-donor differences, the extent of SE-F to enhance HIV-1 infection varies greatly [39]. Although our SE-F samples exerted weak enhancement of viral infection, the pellet of SE-F in the presence of polyanions induced greater increase in susceptibility to HIV-1 infection. "
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    ABSTRACT: Polyanionic candidate microbicides, including cellulose sulfate, carrageenan, PRO 2000, were proven ineffective in preventing HIV-1 transmission and even cellulose sulfate showed increased risk of HIV acquisition in the Phase III efficacy trials. Semen plays critical roles in HIV-1 sexual transmission. Specifically, amyloid fibrils formed by fragments of prostatic acidic phosphatase (PAP) in semen termed semen-derived enhancer of virus infection (SEVI) could drastically enhance HIV-1 infection. Here we investigated the interaction between polyanions and PAP248-286, a prototype peptide of SEVI, to understand the possible cause of polyanionic candidate microbicides to fail in clinical trials. We found anionic polymers could efficiently promote SEVI fibril formation, most likely mediated by the natural electrostatic interaction between polyanions and PAP248-286, as revealed by acid native PAGE and Western blot. The overall anti-HIV-1 activity of polyanions in the presence or absence of PAP248-286 or semen was evaluated. In the viral infection assay, the supernatants of polyanions/PAP248-286 or polyanions/semen mixtures containing the free, unbound polyanionic molecules showed a general reduction in antiviral efficacy, while the pellets containing amyloid fibrils formed by the polyanion-bound PAP248-286 showed aggravated enhancement of viral infection. Collectively, from the point of drug-host protein interaction, our study revealed that polyanions facilitate SEVI fibril formation to promote HIV-1 infection, thus highlighting a molecular mechanism underlying the failure of polyanions in clinical trials and the importance of drug-semen interaction in evaluating the anti-HIV-1 efficacy of candidate microbicides.
    PLoS ONE 03/2013; 8(3):e59777. DOI:10.1371/journal.pone.0059777 · 3.23 Impact Factor
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