Observations on recovery from and recurrence of HSV-2 infections in adult mice that were rescued from lethal vaginal infection by antiviral therapy

Abstract

An adult mouse model for studies of latency and recurrence after vaginal HSV-2 infection is not available at present, largely because the infection kills most mice within 14 days. We describe here an antiviral therapy that rescues most vaginally infected mice from death. Vaginally infected mice were nearly all rescued by combined treatment with one dose of monoclonal anti-HSV glycoprotein D 3 days after infection plus valacyclovir in the drinking water on days 3, 4, 5, 7, 9, 11, 13, and 15 after infection. At 60 days after infection, PCR measurements revealed that most rescued mice had viral DNA in their lumbosacral dorsal root ganglia, lumbosacral spinal cords, and paracervical autonomic ganglia, consistent with the possibility that latent infections were established. At this time, immunolabeling revealed CD45+ lymphoid cells in these neural tissues in rescued mice but not in normal control mice. In vivo depletion of T lymphocytes with monoclonal antibodies caused a recurrence of herpes illness symptoms earlier and in a larger proportion of rescued mice than was observed in non-depleted rescued mice. Interestingly, many rescued mice (46/114) spontaneously developed a syndrome of typical herpes illness symptoms that began with ruffled fur on a mouse that previously had sleek fur and progressed to arched backs, feeble gait, hindlimb paralysis, and death or euthanasia, or in some cases to recovery to health. This high incidence of apparent spontaneous recurrence of HSV-2 infection in rescued mice suggests that it may be possible, with some refinement of the procedure, to obtain an effective adult mouse model for studies of therapeutic vaccination to inhibit or prevent HSV-2 recurrence after genital tract infection.

Use of Transcriptional Profiling to Delineate the Initial Response of Mice to Intravaginal Herpes Simplex Virus Type 2 Infection

“…While our microarray analyses showed ivag infection of mice with 10 4 pfu WT HSV-2 elicits exuberant antiviral immunity, previous studies found this response was unable to prevent mice from developing fatal encephalopathy (11,14,16). Conversely, earlier work also revealed that ivag administration of poly I:C to C57BL/6 mice before or concomitant with HSV-2 infection prevents genital pathology and encephalopathy (1,5).…”

“…hile intravaginal (ivag) herpes simplex virus type 2 (HSV-2) infection of mice causes a fatal encephalopathy that restricts use of this model in HSV latency studies (14), this experimental infection has helped illuminate mammalian antiviral host defense. As examples, inflammatory monocyte recruitment to the vagina during primary HSV-2 infection was shown requisite for formation of optimal T H 1 immunity (6), and CD4 + regulatory T cells were shown to strengthen antiviral defense by coordinating trafficking of effector cells from lymph nodes to HSV-infected vaginal tissue (10).…”

Recurrent vaginal shedding of herpes simplex type 2 virus in the mouse and effects of antiviral therapy

“…In a previous study, Parr and Parr (Parr et al, 2005) reported that BALB/c mice treated with anti-HSV antibody and VACV also survived an intravaginal strain 333 HSV-2 infection and developed a persistent infection in the DRG. Although they did not evaluate the animals for recurrent shedding, they reported that rescued animals often developed typical symptoms of primary disease including hindlimb paralysis that often lead to death after 39–160 days following vaginal inoculation.…”

“…Recurrence of infectious virus was even further pronounced when mice were subjected to immunosuppression during the VACV treatment period (Field et al, 1995); (Thackray and Field, 1997). A more recent study has shown that mice receiving antiviral therapy with VACV and a monoclonal antibody to gD2 can survive primary genital HSV-2 disease and occasionally exhibit symptoms indicative of recurrent genital disease several weeks after inoculation, and that in vivo depletion of T cells with monoclonal antibodies caused an increase in the incidence of the recurrence of herpes symptoms (Parr et al, 2005). These studies indicate that HSV-2 can establish a latent or persistent infection in mice and can undergo spontaneous reactivation which then can result in the recurrence of infectious virus.…”

HSV Type 2 Infection Increases HIV DNA Detection in Vaginal Tissue of Mice Expressing Human CD4 and CCR5

“…Potential advantages of this model when compared with the humanized mouse models for studies of vaginal HIV infection include the ability to cross it with other genetically altered mouse strains and the relatively simple maintenance of the mice. The model could also potentially be used to assess the effects of latent HSV-2 infection on HIV susceptibility [38]. …”