Abstract
BackgroundSemen is a critical vector for human immunodeficiency virus (HIV) sexual transmission and harbors seminal amyloid fibrils that can markedly enhance HIV infection. Semen-derived enhancer of viral infection (SEVI) is one of the best-characterized seminal amyloid fibrils. Due to their highly cationic properties, SEVI fibrils can capture HIV virions, increase viral attachment to target cells, and augment viral fusion. Some studies have reported that myricetin antagonizes amyloid β-protein (Aβ) formation; myricetin also displays strong anti-HIV activity in vitro.ResultsHere, we report that myricetin inhibits the formation of SEVI fibrils 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 fibrils and to influence the activity of SEVI in promoting HIV-1 infection. Moreover, myricetin showed synergistic effects against HIV-1 infection in combination with other antiretroviral drugs in semen.ConclusionsIncorporation 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.
Highlights
Semen is a critical vector for human immunodeficiency virus (HIV) sexual transmission and harbors seminal amyloid fibrils that can markedly enhance HIV infection
Myricetin inhibits the formation of Semen-derived enhancer of viral infection (SEVI) fibrils and other seminal fibrils Thioflavin T (ThT), a dye that is commonly used in the detection of amyloid fibrils, can intercalate into the β-sheet structure of amyloid fibrils, resulting in enhanced fluorescence and a characteristic redshift in the emission spectrum
To evaluate the effects of myricetin on the formation of SEVI fibrils by PAP248–286, we collected PAP248–286 aggregates formed in the presence or absence of various concentrations of myricetin at different time points and monitored them using both ThT fluorescence and Congo red staining assays
Summary
Semen is a critical vector for human immunodeficiency virus (HIV) sexual transmission and harbors seminal amyloid fibrils that can markedly enhance HIV infection. Semen-derived enhancer of viral infection (SEVI) is one of the best-characterized seminal amyloid fibrils. Eliminating seminal amyloid fibrils by antagonizing fibril formation or enhancing the degradation of mature endogenous fibrils can massively reduce any viral infection enhancement [9,10,11]. This strategy might be advantageous because it targets host factors rather than the virus itself
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