The Humoral Immune Response to Kaposi\u27s Sarcoma-Associated Herpesvirus and Its Links to Viral Transmission and Pathogenesis

Kaposi sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus-8, is the etiological agent of Kaposi sarcoma as well as the lymphoblastoid disorders primary effusion lymphoma and multicentric Castleman’s disease. Though immune dysregulation is known to play an important role in the development of KSHV-associated malignancies, the critical components of this responses remain unclear. The objective of this project was to further characterize the humoral immune response among infected individuals and investigate its role in reducing transmission and disease pathogenesis. In order to investigate what role the humoral response might play in transmission, longitudinal responses were characterized in a cohort of Zambian mothers. Higher KSHV binding titers were found among mothers of children who did not acquire KSHV, compared to mothers of KSHV positive children, however, very few of the mothers studied had detectable neutralizing antibodies and there was no difference in the prevalence between groups. The rarity of neutralizing antibodies among asymptomatic KSHV seropositive individuals suggests a role for non-neutralizing antibodies, such as ADCC, in disease mitigation. Therefore, a KSHV specific ADCC was developed to test patient plasma for ADCC activity. ADCC mediating antibodies were found in KSHV seropositive individuals, but there was no difference in prevalence or magnitude of ADCC activity between KS cases and asymptomatic controls. To further determine the repertoire of the humoral immune response and investigate whether specific antibodies could play a protective role against KSHV, monoclonal antibodies generated from infected individuals will be needed. As no fully human monoclonal antibodies against KSHV currently exist, a protocol was established to clone antibodies from KS patients known to have high levels of KSHV neutralizing antibodies. The initial antibody clone generated was not KSHV specific, however the protocol is in place to enable large scale antibody production. Taken all together, the results presented here imply that a strong humoral response may help reduce transmission, however, antibodies alone are insufficient to prevent disease development. More research into the repertoire of the anti-KSHV response and their antigen specificities is needed to better understand the role of antibodies and to work towards therapeutics or a vaccine