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Polyphenylene carboxymethylene (PPCM) in vitro antiviral efficacy against Ebola virus in the context of a sexually transmitted infection.

ABSTRACT: Ebola virus disease (EVD) is caused by Ebola virus (EBOV) and characterized in humans by hemorrhagic fever with high fatality rates. Human-to-human EBOV transmission occurs by physical contact with infected body fluids, or indirectly by contaminated surfaces. Sexual transmission is a route of infection only recently documented despite isolating EBOV virus or genome in the semen since 1976. Data on dissemination of EBOV from survivors remain limited and EBOV pathogenesis in humans following sexual transmission is unknown. The in vitro antiviral efficacy of polyphenylene carboxymethylene (PPCM) against EBOV was investigated considering the limited countermeasures available to block infection through sexual intercourse. PPCM is a vaginal topical contraceptive microbicide shown to prevent sexual transmission of HIV, herpes virus, and bacterial infections in several different models. Here we demonstrate its antiviral activity against EBOV. No viral replication was detected in the presence of PPCM in cell culture, including vaginal epithelial (VK2/E6E7) cells. Specifically, PPCM reduced viral attachment to cells by interfering with EBOV glycoprotein, and possibly through binding the cell surface glycosaminoglycan heparan sulfate important in the infection process. EBOV-infected VK2/E6E7 cells were found to secrete type III interferon (IFN), suggesting activation of distinct PRRs or downstream signaling factors from those required for type I and II IFN. The addition of PPCM following cell infection prevented notably the increase of these inflammation markers. Therefore, PPCM could potentially be used as a topical microbicide to reduce transmission by EBOV-positive survivors during sexual intercourse.

SUBMITTER: Escaffre O

PROVIDER: S-EPMC6765433 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Polyphenylene carboxymethylene (PPCM) in vitro antiviral efficacy against Ebola virus in the context of a sexually transmitted infection.

Escaffre Olivier O Juelich Terry L TL Freiberg Alexander N AN

Antiviral research 20190724

Ebola virus disease (EVD) is caused by Ebola virus (EBOV) and characterized in humans by hemorrhagic fever with high fatality rates. Human-to-human EBOV transmission occurs by physical contact with infected body fluids, or indirectly by contaminated surfaces. Sexual transmission is a route of infection only recently documented despite isolating EBOV virus or genome in the semen since 1976. Data on dissemination of EBOV from survivors remain limited and EBOV pathogenesis in humans following sexua ...[more]

PMID: 31351092

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Project description:BACKGROUND:Despite repeated outbreaks, in particular the devastating 2014-2016 epidemic, there is no effective treatment validated for patients with Ebola virus disease (EVD). Among the drug candidates is the broad-spectrum polymerase inhibitor favipiravir, which showed a good tolerance profile in patients with EVD (JIKI trial) but did not demonstrate a strong antiviral efficacy. In order to gain new insights into the antiviral efficacy of favipiravir and improve preparedness and public health management of future outbreaks, we assess the efficacy achieved by ascending doses of favipiravir in Ebola-virus-infected nonhuman primates (NHPs). METHODS AND FINDINGS:A total of 26 animals (Macaca fascicularis) were challenged intramuscularly at day 0 with 1,000 focus-forming units of Ebola virus Gabon 2001 strain and followed for 21 days (study termination). This included 13 animals left untreated and 13 treated with doses of 100, 150, and 180 mg/kg (N = 3, 5, and 5, respectively) favipiravir administered intravenously twice a day for 14 days, starting 2 days before infection. All animals left untreated or treated with 100 mg/kg died within 10 days post-infection, while animals receiving 150 and 180 mg/kg had extended survival (P < 0.001 and 0.001, respectively, compared to untreated animals), leading to a survival rate of 40% (2/5) and 60% (3/5), respectively, at day 21. Favipiravir inhibited viral replication (molecular and infectious viral loads) in a drug-concentration-dependent manner (P values < 0.001), and genomic deep sequencing analyses showed an increase in virus mutagenesis over time. These results allowed us to identify that plasma trough favipiravir concentrations greater than 70-80 ?g/ml were associated with reduced viral loads, lower virus infectivity, and extended survival. These levels are higher than those found in the JIKI trial, where patients had median trough drug concentrations equal to 46 and 26 ?g/ml at day 2 and day 4 post-treatment, respectively, and suggest that the dosing regimen in the JIKI trial was suboptimal. The environment of a biosafety level 4 laboratory introduces a number of limitations, in particular the difficulty of conducting blind studies and performing detailed pharmacological assessments. Further, the extrapolation of the results to patients with EVD is limited by the fact that the model is fully lethal and that treatment initiation in patients with EVD is most often initiated several days after infection, when symptoms and high levels of viral replication are already present. CONCLUSIONS:Our results suggest that favipiravir may be an effective antiviral drug against Ebola virus that relies on RNA chain termination and possibly error catastrophe. These results, together with previous data collected on tolerance and pharmacokinetics in both NHPs and humans, support a potential role for high doses of favipiravir for future human interventions.

Project description:Risk and protective processes are integrated developmental processes that directly or indirectly affect behavioral outcomes. A better understanding of these processes is needed, in order to gauge their contribution to sexual risk behaviors. This retrospective cross-sectional study modeled the ecodevelopmental chain of relationships to examine the social contexts of African-American (AA) adolescents associated with sexually transmitted disease (STD)- and HIV-risk behaviors. We used data from 1,619 AA adolescents with an average age of 16±1.8 years obtained from the first wave of the National Longitudinal Study of Adolescent Health for this study. Confirmatory factor analysis followed by structural equation modeling was conducted to identify the latent constructs that reflect the social-interactional components of the ecodevelopmental theory. Among contextual factors, findings indicated that a feeling of love from father, school, religion, and parent attitudes toward adolescent sexual behavior were all factors that played significant roles in the sexual behavior of AA adolescents. AA adolescents who reported feeling love from their father, feeling a strong negative attitude from their parents toward having sex at a very young age, and having a strong bond with school personnel were associated with better health statuses. The level of parents' involvement in their children's lives was reflected in the adolescents' feeling of love from parents and moderated by their socioeconomic status. Being male, attaining increased age, and being a sexual minority were associated with higher likelihood of exhibiting risky sexual behavior. In contrast, higher socioeconomic status and fathers' level of involvement were indirectly associated with reduced STD/HIV-related sexual risk behavior. In conclusion, our findings suggest that interventions aimed at maximal protection against STD/HIV-related risk behavior among AA adolescents should adopt both self- and context-based strategies that promote positive functioning in the family, school, and peer microsystems.

Dataset Information

Polyphenylene carboxymethylene (PPCM) in vitro antiviral efficacy against Ebola virus in the context of a sexually transmitted infection.

Publications

Polyphenylene carboxymethylene (PPCM) in vitro antiviral efficacy against Ebola virus in the context of a sexually transmitted infection.

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