Cercopithecine herpesvirus 1 (B virus) pathogenesis and vaccine development.

摘要

Cercopithecine herpesvirus 1 (B virus) is an alphaherpesvirus that naturally infects rhesus macaques for life. While disease expression is limited in its natural host, transmission of B virus to humans results in severe disease with dissemination to the nervous system and a high fatality rate. Approximately 90% of macaques used for medical research are infected with B virus and pose a serious threat to humans who work with them. Protective guidelines have limited the incidence of human transmission, but recent fatal cases of human B virus infection demonstrate the need for additional measures. The focus of this project was the characterization of key aspects of B virus biology, including the frequency of virus reactivation and host immune responses following natural infection and vaccination. Application of a sensitive, quantitative PCR technique revealed asymptomatic B virus reactivation in monkeys surveyed during the breeding season, but not at other times of the year. The results confirmed previous estimates of infrequent B virus reactivation, but suggested that seasonal stresses may be involved in reactivation mechanisms. Macaques naturally infected with B virus developed T lymphocyte proliferative responses and maintained antibody titers for life. Assessment of these immune responses was made using the closely related, but non-biohazardous herpesvirus papio 2 as antigen. Using anti-B virus immune responses as a threshold, a candidate vaccine was developed. Mice and macaques immunized with a B virus glycoprotein B expression plasmid developed anamnestic IgG neutralizing antibody responses. These results demonstrated that DNA plasmids expressing B virus antigens are a viable tool to vaccinate macaques. In addition to elucidating key aspects of B virus biology in its natural host, technological developments of this project provide a foundation for large-scale studies of B virus pathogenesis, testing vaccine strategies, and the promotion of B virus infection in the rhesus macaque as a model system for human herpes simplex virus infection.