MOLECULAR PATHOGENESIS OF VARICELLA ZOSTER VIRUS INFECTION

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Monkeys can be infected with simian varicella virus (SVV), with clinical, pathological, immunological and virological features virtually identical to those of VZV infection in humans. Also similar to humans, following 8-12 weeks post infection, the virus becomes latent in the dorsal root ganglia and have the potential to reactivate. Our earlier work developed a latency/reactivation model in the African green monkey. Latently-infected AGM were tested by immunosuppression and X-irradiation and were shown to initiate SVV reactivation. The nonhuman primate model was originally developed in the AGM as a natural transmission model. SVV-seronegative monkeys were exposed as cagemates to other monkeys that had been inoculated with SVV. The inoculated monkeys became infected, developed chickenpox but virus persisted for weeks/months in the peripheral circulation, lungs, and liver. The exposed monkeys, however, developed chickenpox but were able to clear virus from the bloodstream quickly and by 8-12 weeks, virus was found only in nerve tissue but not in lung or liver. A typical study consisted of 8 animals: 3 inoculated and 5 exposed. A recent study by Messaoudi et al., 2009, proposed that SVV infection in rhesus macaque results in a similar latency rather than persistent infection. Due to the needed use of increased numbers of animals to accomplish natural exposure, we wanted to confirm these findings. A small study was conducted in rhesus macaque to test the ability of another species to develop latency following direct inoculation of SVV. Two seronegative rhesus macaques were intratracheal inoculated with 1 x 10e4 SVV and followed for virolgical and clinical findings. Both animals were infected, developed typical chickenpox rash, and circulating virus peaking at d12 post inoculation. We followed the animals for 14 weeks and demonstrated significant clearance of virus by 8 weeks suggesting latency. We conducted necropsy of both animals and are currently assessing levels of virus in lung, liver and ganglia for final confirmation of latency. If they are finally confirmed, we will switch to the rhesus for use in conducting the remaining studies proposed in this grant.