Semen-Derived Amyloid Fibrils Drastically Enhance HIV Infection

Institute of Virology, University Clinic of Ulm, 89081 Ulm, Germany.
Cell (Impact Factor: 32.24). 01/2008; 131(6):1059-71. DOI: 10.1016/j.cell.2007.10.014
Source: PubMed


Sexual intercourse is the major route of HIV transmission. To identify endogenous factors that affect the efficiency of sexual viral transmission, we screened a complex peptide/protein library derived from human semen. We show that naturally occurring fragments of the abundant semen marker prostatic acidic phosphatase (PAP) form amyloid fibrils. These fibrils, termed Semen-derived Enhancer of Virus Infection (SEVI), capture HIV virions and promote their attachment to target cells, thereby enhancing the infectious virus titer by several orders of magnitude. Physiological concentrations of SEVI amplified HIV infection of T cells, macrophages, ex vivo human tonsillar tissues, and transgenic rats in vivo, as well as trans-HIV infection of T cells by dendritic or epithelial cells. Amyloidogenic PAP fragments are abundant in seminal fluid and boost semen-mediated enhancement of HIV infection. Thus, they may play an important role in sexual transmission of HIV and could represent new targets for its prevention.

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    • "SEVI-mediated enhancement of HIV infection is evident in vitro starting at a concentration of 2 μg/mL and increases with concentration up to at least 50 μg/mL (Munch et al., 2007). The amount of SEVI reported by Munch et al. (2007) to be present in semen was "
    Article: ID: 41

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    • "Thereafter, a CCR5-tropic lab-adapted virus or a transmitted/founder virus were incubated with 10% of these solutions followed by infection of TZM-bl cells. Consistent with previous studies (M ¨ unch et al., 2007; Hauber et al., 2009; Roan et al., 2009; Kim et al., 2010), seminal plasma enhanced infection of both viruses by 10-or 8-fold, respectively (Figure 9B). CLR01 decreased viral infectivity enhancement in a concentration-dependent manner, while CLR03 had no effect on semenmediated infection enhancement (Figure 9B). "
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    ABSTRACT: Semen is the main vector for HIV transmission and contains amyloid fibrils that enhance viral infection. Available microbicides that target viral components have proven largely ineffective in preventing sexual virus transmission. In this study, we establish that CLR01, a 'molecular tweezer' specific for lysine and arginine residues, inhibits the formation of infectivity-enhancing seminal amyloids and remodels preformed fibrils. Moreover, CLR01 abrogates semen-mediated enhancement of viral infection by preventing the formation of virion-amyloid complexes and by directly disrupting the membrane integrity of HIV and other enveloped viruses. We establish that CLR01 acts by binding to the target lysine and arginine residues rather than by a non-specific, colloidal mechanism. CLR01 counteracts both host factors that may be important for HIV transmission and the pathogen itself. These combined anti-amyloid and antiviral activities make CLR01 a promising topical microbicide for blocking infection by HIV and other sexually transmitted viruses.
    Full-text · Article · Aug 2015 · eLife Sciences
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    • "One mechanism by which semen could enhance sexual transmission of HIV was demonstrated by Munch and colleagues in 2007 [70]. To identify natural agents that might play a role in sexual transmission of HIV, Munch and colleagues developed a complex peptide/protein library derived from human seminal plasma which was screened for novel inhibitors and enhancers of HIV infection. "
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