Neurotropic viral disease is an important cause of morbidity and mortality in man. The present application focuses on the protective role of antibodies in herpes simplex virus (HSV) infections, which are among the most prevalent of human maladies. Although the most common clinical manifestations of HSV are vesicular eruptions of the skin and mucous membranes, HSV can cause severe keratitis, encephalitis, and disseminated illness in the newborn. Furthermore, in immunodepressed patients, herpetic manifestations are particularly severe. The emergence of drug-resistant strains of HSV in these patients, after prolonged therapy, is of serious concern both in terms of clinical management and of viral ecology. The host immune response plays a crucial role in the recovery from primary HSV infections and in the establishment and maintenance of HSV latency. However, most individuals' natural immunity only provides partial protection from recurrence and reinfection. Therefore, it is of paramount importance to dissect the role of the different components of the immune response in order to understand which aspects are most crucial and whether those components can be boosted to a level sufficient to confer protection. The applicants propose to isolate human monoclonal antibodies from combinatorial Fab libraries and to characterize their mechanisms of action by virological, biochemical, and morphologic methods. They this approach, they have recently generated these antibodies against many pathogenic viruses, including HSV. Some of these anti bodies displayed potent antiviral activities in both in vitro and in vivo paradigms. Therefore, the investigators hypothesize that some antibodies generated in the natural immune response can confer a substantial degree of neuroprotection. The proposed research aims to shed light on the molecular mechanisms behind the protective activity of antibodies against HSV. Such information will be of general importance in understanding the role of the immune system in neurotropic viral infection. In addition, the proposed research aims to generate antibodies that will be potentially useful in the prophylaxis and treatment of HSV infections.
