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2. Amphipathic DNA polymers exhibit antiviral activity against systemic Murine Cytomegalovirus infection

Author

Juteau Jean-Marc, Flamand Louis, Cummins James, Sewell Andrea P, Bravo Fernando J, Cardin Rhonda D, Bernstein David I, and Vaillant Andrew

Subjects
Infectious and parasitic diseases, RC109-216
Abstract

Abstract Background Phosphorothioated oligonucleotides (PS-ONs) have a sequence-independent, broad spectrum antiviral activity as amphipathic polymers (APs) and exhibit potent in vitro antiviral activity against a broad spectrum of herpesviruses: HSV-1, HSV-2, HCMV, VZV, EBV, and HHV-6A/B, and in vivo activity in a murine microbiocide model of genital HSV-2 infection. The activity of these agents against animal cytomegalovirus (CMV) infections in vitro and in vivo was therefore investigated. Results In vitro, a 40 mer degenerate AP (REP 9) inhibited both murine CMV (MCMV) and guinea pig CMV (GPCMV) with an IC50 of 0.045 μM and 0.16 μM, respectively, and a 40 mer poly C AP (REP 9C) inhibited MCMV with an IC50 of 0.05 μM. Addition of REP 9 to plaque assays during the first two hours of infection inhibited 78% of plaque formation whereas addition of REP 9 after 10 hours of infection did not significantly reduce the number of plaques, indicating that REP 9 antiviral activity against MCMV occurs at early times after infection. In a murine model of CMV infection, systemic treatment for 5 days significantly reduced virus replication in the spleens and livers of infected mice compared to saline-treated control mice. REP 9 and REP 9C were administered intraperitoneally for 5 consecutive days at 10 mg/kg, starting 2 days prior to MCMV infection. Splenomegaly was observed in infected mice treated with REP 9 but not in control mice or in REP 9 treated, uninfected mice, consistent with mild CpG-like activity. When REP 9C (which lacks CpG motifs) was compared to REP 9, it exhibited comparable antiviral activity as REP 9 but was not associated with splenomegaly. This suggests that the direct antiviral activity of APs is the predominant therapeutic mechanism in vivo. Moreover, REP 9C, which is acid stable, was effective when administered orally in combination with known permeation enhancers. Conclusion These studies indicate that APs exhibit potent, well tolerated antiviral activity against CMV infection in vivo and represent a new class of broad spectrum anti-herpetic agents.

Published
2009
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19. A helicase-primase drug candidate with sufficient target tissue exposure affects latent neural herpes simplex virus infections

Author

Gege, Christian, primary, Bravo, Fernando J., additional, Uhlig, Nadja, additional, Hagmaier, Timo, additional, Schmachtenberg, Rosanne, additional, Elis, Julia, additional, Burger-Kentischer, Anke, additional, Finkelmeier, Doris, additional, Hamprecht, Klaus, additional, Grunwald, Thomas, additional, Bernstein, David I., additional, and Kleymann, Gerald, additional

Published
2021
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25. A vaccine containing highly purified virus particles in adjuvant provides high level protection against genital infection and disease in guinea pigs challenged intravaginally with homologous and heterologous strains of herpes simplex virus type 2

Author

Bernstein, David I., primary, Morello, Christopher S., additional, Cardin, Rhonda D., additional, Bravo, Fernando J., additional, Kraynyak, Kimberly A., additional, and Spector, Deborah H., additional

Published
2020
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32. Inhibition of LSD1 reduces herpesvirus infection, shedding, and recurrence by promoting epigenetic suppression of viral genomes

Author

Hill, James M., primary, Quenelle, Debra C., additional, Cardin, Rhonda D., additional, Vogel, Jodi L., additional, Clement, Christian, additional, Bravo, Fernando J., additional, Foster, Timothy P., additional, Bosch-Marce, Marta, additional, Raja, Priya, additional, Lee, Jennifer S., additional, Bernstein, David I., additional, Krause, Philip R., additional, Knipe, David M., additional, and Kristie, Thomas M., additional

Published
2014
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33. Topical SMIP-7.7, a Toll–Like Receptor 7 Agonist, Protects against Genital Herpes Simplex Virus Type-2 Disease in the Guinea Pig Model of Genital Herpes

Author

Bernstein, David I, primary, Cardin, Rhonda D, additional, Bravo, Fernando J, additional, Earwood, Julie, additional, Clark, Jennifer R, additional, Li, Yongkai, additional, Mishra, Pranab, additional, Li, Chun, additional, Nayak, Bishnu P, additional, Miller, Andrew T, additional, Wu, Tom Y-H, additional, Cooke, Michael P, additional, and Valiante, Nicholas M, additional

Published
2014
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34. An Adjuvanted Herpes Simplex Virus 2 Subunit Vaccine Elicits a T Cell Response in Mice and Is an Effective Therapeutic Vaccine in Guinea Pigs

Author

Skoberne, Mojca, primary, Cardin, Rhonda, additional, Lee, Alexander, additional, Kazimirova, Ana, additional, Zielinski, Veronica, additional, Garvie, Danielle, additional, Lundberg, Amy, additional, Larson, Shane, additional, Bravo, Fernando J., additional, Bernstein, David I., additional, Flechtner, Jessica B., additional, and Long, Deborah, additional

Published
2013
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43. Oral Hexadecyloxypropyl-Cidofovir Therapy in Pregnant Guinea Pigs Improves Outcome in the Congenital Model of Cytomegalovirus Infection

Author

Bravo, Fernando J., Bernstein, David I., Beadle, James R., Hostetler, Karl Y., and Cardin, Rhonda D.

Abstract

ABSTRACTCytomegalovirus (CMV) infection is the leading cause of congenital infection, producing both sensorineural hearing loss and mental retardation. We evaluated the in vivoefficacy of an orally bioavailable analog of cidofovir, hexadecyloxypropyl-cidofovir (HDP-CDV), against guinea pig CMV (GPCMV) in a guinea pig model of congenital CMV infection. HDP-CDV exhibited antiviral activity against GPCMV with a 50% effective concentration (EC50) of 0.004 μM ± 0.001 μM. To evaluate in vivoefficacy, pregnant Hartley guinea pigs were inoculated with GPCMV during the late second/early third trimester of gestation. Animals were administered 20 mg HDP-CDV/kg body weight orally at 24 h postinfection (hpi) and again at 7 days postinfection (dpi) or administered 4 mg/kg HDP-CDV orally each day for 5 days or 9 days. Virus levels in dam and pup tissues were evaluated following delivery, or levels from dam, placenta, and fetal tissues were evaluated following sacrifice of dams at 10 dpi. All HDP-CDV regimens significantly improved pup survival, from 50 to 60% in control animals to 93 to 100% in treated animals (P≤ 0.019). Treatment with 20 mg/kg HDP-CDV significantly reduced the viral load in pup spleen (P= 0.017) and liver (P= 0.029). Virus levels in the placenta were significantly reduced at 10 dpi following daily treatment with 4 mg/kg HDP-CDV for 5 or 9 days. The 9-day treatment also significantly reduced the viral levels in the dam spleen and liver. Although the 4-mg/kg treatment improved pup survival, virus levels in the fetal tissues were similar to those in control tissues. Taken together, HDP-CDV shows potential as a well-tolerated antiviral candidate for treatment of congenital human CMV (HCMV) infection.

Published
2010
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