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: 4.77). 06/2010; 7:55. 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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Available from: Nadia R Roan, Aug 18, 2015
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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. DOI:10.1111/j.2047-2927.2013.00099.x · 3.37 Impact Factor
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    • "Infectivity assays were essentially performed as described (Kim et al., 2010; Roan et al., 2009). HIV-1 from the supernatant of transfected 293T cells was diluted to 0.1 mg/ml p24 and pretreated for 5 min with peptide or semen/ seminal fluid at the indicated concentrations. "
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    ABSTRACT: Semen serves as a vehicle for HIV and promotes sexual transmission of the virus, which accounts for the majority of new HIV cases. The major component of semen is the coagulum, a viscous structure composed predominantly of spermatozoa and semenogelin proteins. Due to the activity of the semen protease PSA, the coagulum is liquefied and semenogelins are cleaved into smaller fragments. Here, we report that a subset of these semenogelin fragments form amyloid fibrils that greatly enhance HIV infection. Like SEVI, another amyloid fibril previously identified in semen, the semenogelin fibrils exhibit a cationic surface and enhance HIV virion attachment and entry. Whereas semen samples from healthy individuals greatly enhance HIV infection, semenogelin-deficient semen samples from patients with ejaculatory duct obstruction are completely deficient in enhancing activity. Semen thus harbors distinct amyloidogenic peptides derived from different precursor proteins that commonly enhance HIV infection and likely contribute to HIV transmission.
    Cell host & microbe 12/2011; 10(6):541-50. DOI:10.1016/j.chom.2011.10.010 · 12.19 Impact Factor
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    • "PAP 248–286 is inactive in the monomeric state and must first aggregate to form the active SEVI (semen enhancer of viral infection) form to promote viral infection [4] [6] [9]. While many species of aggregated PAP 248–286 appears to be active, PAP 248–286 is most active in the form of large aggregates with the characteristic β-sheet conformation of amyloid proteins [4] [10]. Since the cross β-sheet structural motif is common to all amyloid proteins but the ability of amyloid fibers from other proteins to enhance viral infection is minor in comparison to SEVI fibers from PAP 248–286 , a structural understanding of SEVI and its precursors at the atomic level is necessary to understand its mechanism of action [4] [11]. "
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    ABSTRACT: Amyloid fibers in human semen known as SEVI (semen-derived enhancer of viral infection) dramatically increase the infectivity of HIV and other enveloped viruses, which appears to be linked to the promotion of bridging interactions and the neutralization of electrostatic repulsion between the host and the viral cell membranes. The SEVI precursor PAP(248-286) is mostly disordered when bound to detergent micelles, in contrast to the highly α-helical structures found for most amyloid proteins. To determine the origin of this difference, the structures of PAP(248-286) were solved in aqueous solution and with 30% and 50% trifluoroethanol. In solution, pulsed field gradient (PFG)-NMR and (1)H-(1)H NOESY experiments indicate that PAP(248-286) is unfolded to an unusual degree for an amyloidogenic peptide but adopts significantly helical structures in TFE solutions. The clear differences between the structures of PAP(248-286) in TFE and SDS indicate electrostatic interactions play a large role in the folding of the peptide, consistent with the slight degree of penetration of PAP(248-286) into the hydrophobic core of the micelle. This is another noticeable difference between PAP(248-286) and other amyloid peptides, which generally show penetration into at least the headgroup region of the bilayer, and may explain some of the unusual properties of SEVI.
    Biochimica et Biophysica Acta 04/2011; 1808(4):1161-9. DOI:10.1016/j.bbamem.2011.01.010 · 4.66 Impact Factor
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