Neurovirulence and latency of drug‐resistant clinical herpes simplex viruses in animal models

Abstract

Herpes simplex virus (HSV) resistance to acyclovir or foscarnet results from mutations in viral thymidine kinase (TK) and/or DNA polymerase (pol) genes. Replication kinetics and virulence of TK and/or DNA pol clinical mutants were assessed using models of mouse encephalitis and cotton rat genital infection. Replication capacities in Vero cells of a DNA pol altered strain (L850I) and a TK/DNA pol mutant (C467deletion/A912V) were significantly lower than those of unrelated wild-type (WT) strains, while a double DNA pol mutant (S724N/P920S) demonstrated replication kinetics similar to the WT. The replication of a TK-deficient mutant (G439.5addition) was impaired (low m.o.i.) or unaltered (high m.o.i.) compared to that of a WT virus depending on the viral inoculum. Compared to a survival rate of 6% for mice infected intranasally with WT HSV-1 or -2 viruses, G439.5add, C467deletion/A912V and L850I strains were associated with survival rates of 100% (P < 0.05) whereas mice infected with the S724N/P920S mutant had a survival rate of 33% (P = 0.08). Brain viral titers were higher in mice infected with WT HSV-1 or -2 strains and the double DNA pol mutant. All strains except the DNA pol mutant L850I were able to establish latency in the dorsal root ganglia of cotton rats. A good correlation was generally found between replication kinetics of DNA pol mutants and their neurovirulence potential in mice whereas such correlation was not straightforward for TK mutants.

Prevalence of herpes simplex virus type 1 glycoprotein G (gG) and gI genotypes in patients with different herpetic diseases during the last four decades

“…Interestingly, no isolate was assigned as genotype A that represents nearly 50% of all strains included in this study. Using animal models, previous reports have shown that clinical HSV‐1 isolates differ in virulence [Reefschläger et al, 1986; Bower et al, 1999; Dambrosi et al, 2010]. However, Norberg et al [2004] were unable to demonstrate an association between specific sequences of gG as well as gI genes and anatomical sites of lesions, including brain.…”

Resistance of Herpes Simplex Viruses to Nucleoside Analogues: Mechanisms, Prevalence, and Management

“…Neuroinvasiveness is expected to correlate with viral fitness, so that highly replicating viruses would be more neurovirulent. Recently, it has been shown that the degree of neurovirulence of several DNA pol mutants could be generally predicted by their in vitro replicative capacity (67). However, Pelosi et al (163) reported a DNA pol mutant (R842S) that could replicate in the central nervous system but, paradoxically, exhibited attenuated neurovirulence.…”

Virostatic potential of micro–nano filopodia-like ZnO structures against herpes simplex virus-1

“…While acyclovir and related nucleoside analogues provide successful modalities for treatment and suppression, HSV remains highly prevalent worldwide. The emergence of acyclovir-resistant virus strains, ability of virus to uniformly establish latency coupled with adverse effects of available anti-herpetic compounds provides a stimulus for increased search for new effective antiviral agents that target additional steps in viral pathogenesis such as entry (Schutle et al, 2010; Dambrosi et al, 2010). In addition, the current available treatments are unable to destroy HSV completely and therefore virus remains dormant and keeps activating from time to time to cause various clinical manifestations.…”