Clinicopathological Characterization of Monkey B Virus (Cercopithecine Herpesvirus 1) Infection in Mice

Summary

The purpose of this study was to establish a small animal model for monkey B virus (BV) infection. Mice were inoculated intramuscularly with several BV isolates. Comparisons were based upon the doses required to produce infection (ID₅₀), non-central nervous system (CNS) clinical disease (CS₅₀), CNS disease (CNSD₅₀) and lethal effect (LD₅₀). Strains differed in respect of the dose required to produce clinical disease in BALB/c mice. C57BL/6 mice were more resistant than BALB/c mice to CNS disease. Skin lesions at the inoculation site consisted of epidermal necrosis, ulceration, serocellular crusts and underlying dermatitis. CNS lesions included marked inflammation in the ipsilateral dorsal root ganglion and lumbar spinal cord (point of viral entry). The distribution of the lumbar spinal cord lesions suggested viral entry via sensory afferent neurons, ventral motor tracts, or both. The lesions in the more cranial spinal cord segments suggested ascension to the brain via bilateral spinothalamic and spinoreticular tracts. Brain lesions included encephalitis with neuronal necrosis and white matter destruction located consistently at the base of the brainstem, the reticular system, and rostrally to the thalamus and hypothalamus. Viral antigen was detected immunohistochemically in the lesions. The results indicated an ascending encephalomyelitis syndrome similar to that produced by BV in man.

Introduction

Monkey B virus (BV; Cercopithecine herpesvirus 1) is an α-herpesvirus of macaque monkeys that is best known for its zoonotic potential. In man, BV results in an ascending encephalomyelitis, which has been responsible for a number of deaths since the first recorded case in 1932 (Gay and Holden, 1933, Sabin and Wright, 1934). Human BV infections usually occur in those who work with macaque monkeys, infection usually being acquired via bites or scratches (Weigler, 1992, Freifeld et al., 1995).

The severe, life-threatening neurovirulence of BV in man is in sharp contrast to the disease syndrome in macaques, in which the clinical signs closely resemble those produced in man by herpes simplex virus (HSV) 1 and 2 (Zwartouw and Boulter, 1984, Zwartouw et al., 1984). These include oral or genital lesions, particularly in primary infection (Palmer, 1987); however, symptomless infection is common. Macaques are often infected as juveniles at the onset of sexual activity (Zwartouw et al., 1984, Weigler, 1992). In infected macaque colonies, the number of animals shedding BV is low (Weir et al., 1993, Huff et al., 2003), but the absence of clinical signs that accompanies reactivation of virus makes recognition of virus-shedding animals impossible.

Due to risks associated with BV research, investigation of the pathogenesis of BV infection has been limited to intermittent descriptions of clinical cases in man (Huff and Barry, 2003) and non-human primates (Loomis et al., 1981, Wilson et al., 1990, Carlson et al., 1997, Thompson et al., 2000) and to a few studies in mice and rabbits. Gosztonyi et al. (1992) described the neuroanatomical spread of BV in the central nervous system (CNS) of mice, concluding that the dissemination of BV was similar to that of other α-herpesviruses in other species. The rabbit has been used occasionally in studies on BV pathogenesis, treatment and vaccination (Benda et al., 1969, Boulter et al., 1980, Zwartouw et al., 1989).

No well-characterized animal model system has ever been developed for BV. As a first step in model development, this paper characterizes baseline parameters of monkey B virus infection in mice, with emphasis on the clinicopathological progression of disease.