The FDA-Approved Drug Nelfinavir Inhibits Lytic Cell-Free but Not Cell-Associated Nonlytic Transmission of Human Adenovirus

• Published in: Antimicrobial agents and chemotherapy Vol. 64; no. 9
• Main Authors: Georgi, Fanny, Andriasyan, Vardan, Witte, Robert, Murer, Luca, Hemmi, Silvio, Yu, Lisa, Grove, Melanie, Meili, Nicole, Kuttler, Fabien, Yakimovich, Artur, Turcatti, Gerardo, Greber, Urs F
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 20.08.2020
• Subjects: Adenoviridae; Adenoviridae Infections; Adenovirus Infections, Human - drug therapy; Adenoviruses, Human; Antiviral Agents; Humans; Nelfinavir - pharmacology; Pharmaceutical Preparations; adenovirus death protein; drug repurposing; antiviral agents; fluorescence imaging; oncolytic virus; plaque assay; compound screening; virus transmission; membrane rupture; cell lysis
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.01002-20

Adenoviruses (AdVs) are prevalent and give rise to chronic and recurrent disease. Human AdV (HAdV) species B and C, such as HAdV-C2, -C5, and -B14, cause respiratory disease and constitute a health threat for immunocompromised individuals. HAdV-Cs are well known for lysing cells owing to the E3 CR1-β-encoded adenovirus death protein (ADP). We previously reported a high-throughput image-based screening framework and identified an inhibitor of HAdV-C2 multiround infection, nelfinavir mesylate. Nelfinavir is the active ingredient of Viracept, an FDA-approved inhibitor of human immunodeficiency virus (HIV) aspartyl protease that is used to treat AIDS. It is not effective against single-round HAdV infections. Here, we show that nelfinavir inhibits lytic cell-free transmission of HAdV, indicated by the suppression of comet-shaped infection foci in cell culture. Comet-shaped foci occur upon convection-based transmission of cell-free viral particles from an infected cell to neighboring uninfected cells. HAdV lacking ADP was insensitive to nelfinavir but gave rise to comet-shaped foci, indicating that ADP enhances but is not required for cell lysis. This was supported by the notion that HAdV-B14 and -B14p1 lacking ADP were highly sensitive to nelfinavir, although HAdV-A31, -B3, -B7, -B11, -B16, -B21, -D8, -D30, and -D37 were less sensitive. Conspicuously, nelfinavir uncovered slow-growing round HAdV-C2 foci, independent of neutralizing antibodies in the medium, indicative of nonlytic cell-to-cell transmission. Our study demonstrates the repurposing potential of nelfinavir with postexposure efficacy against different HAdVs and describes an alternative nonlytic cell-to-cell transmission mode of HAdV.