Efficacy of pritelivir and acyclovir in the treatment of herpes simplex virus infections in a mouse model of herpes simplex encephalitis

Abstract

Pritelivir, a helicase-primase inhibitor, has excellent in vitro and in vivo activity against human herpes simplex virus (HSV). Mice lethally infected with HSV type 1 or 2, including acyclovir-resistant strains, were treated 72 h after infection for 7 days with pritelivir or acyclovir. Both drugs were administered orally twice daily either alone or in combination. Dosages of pritelivir from 0.3 to 30 mg/kg reduced mortality (P < 0.001) against HSV-1, E-377. With an acyclovir resistant HSV-1, 11360, pritelivir at 1 and 3 mg/kg increased survival (P < 0.005). With HSV-2, MS infected mice, all dosages higher than the 0.3 mg/kg dose of pritelivir were effective (P < 0.005). For acyclovir resistant HSV-2, strain 12247, pritelivir dosages of 1-3 mg/kg significantly improved survival (P < 0.0001). Combination therapies of pritelivir at 0.1 or 0.3 mg/kg/dose with acyclovir (10 mg/kg/dose) were protective (P < 0.0001) when compared to the vehicle treated group against HSV-2, strain MS (in line with previous data using HSV-1). An increased mean days to death (P < 0.05) was also observed and was indicative of a potential synergy. Pharmacokinetic studies were performed to determine pritelivir concentrations and a dose dependent relationship was found in both plasma and brain samples regardless of infection status or time of initiation of dosing. In summary, pritelivir was shown to be active when treatment was delayed to 72 h post viral inoculation and appeared to synergistically inhibit mortality in this model in combination with acyclovir. We conclude pritelivir has potent and resistance-breaking antiviral efficacy with potential for the treatment of potentially life-threatening HSV type 1 and 2 infections, including herpes simplex encephalitis.

A Preclinical Model for Studying Herpes Simplex Virus Infection

“…The combination of both drugs showed an augmented, although not statistically significant, effect upon HSV-1 infection compared with the single drug treatment (Figure 4d). These results are in line with mouse data showing that a combination of pritelivir and acyclovir has an additive effect against HSV-2 infection (Quenelle et al, 2018).…”

Herpes simplex virus resistance to antivirals

“…L'AMV présente une CE 50 moyenne de 0,036 µM pour le HSV-1 et une activité 14 fois supérieure à celle du VACV [101]. Leur principal atout est de rester actif sur les virus résistants à l'ACV [102]. De plus, elles possèdent une biodisponibilité de l'ordre de 40% pour l'AMV et de plus de 60% pour le PTV, permettant donc leur administration par voie orale [103,104].…”

The interplay between viruses and TRIM family proteins

“…The human chromosome 11 contains genes on its short arm ( Figure 2) that are found to be involved in antiviral activity. Most of the TRIM genes are localized there including TRIM 3,5,6,21,22,34,66,and 68 and are under heavy positive selective pressure. Some of these genes are also identified as viral restriction factors and TRIM 5, 22, and 34 are potent inhibitors of HIV.…”

“…Apart from IAV, PML, ie, TRIM19, regulates the HSV infection in complex with ND10 which is another nuclear body. Viral regulatory protein, ICPO, localize and bring about the degradation of PML, but studies conducted in BHK cells have shown that ICPO negative mutant of HSV‐1 is susceptible to the action of PML as the visible decrease in plaque formation and gene expression is observed …”