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.
Highlights
Heterosexual intercourse accounts for more than 80% of new HIV infection worldwide [1]
In view of the unique environment where the drug exerts its pharmaceutical effect during sexual intercourse, the biological interaction with seminal protein should be a significant determinant to evaluate the efficacy of a candidate microbicide
Our results for the first time demonstrated that polyanionic candidate microbicides accelerated semen-derived amyloid fibril formation
Summary
Heterosexual intercourse accounts for more than 80% of new HIV infection worldwide [1]. No candidate microbicide has proceeded from successful clinical trials to licensure, 1% of tenofovir gel showed 39% efficacy among tested women in the recent microbicide trial [5]. The most mentioned polyanionic candidate microbicides include cellulose sulfate, carrageenan, naphthalene sulfonate (PRO 2000), cellulose acetate phthalate (CAP) and polystyrene sulfonate. Three of these have been advanced into Phase III clinical trials. Though the difference was not statistically significant (p = 0.239), use of 2% PRO 2000 gel was terminated at primary safety endpoint. It appeared that increasing dosage of PRO 2000 might implicate trends towards growing risk of HIV-1 transmission
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