Defining Critical Sites of Vulnerability and Correlates of Protection to Kaposi Sarcoma Associated Herpesvirus to Inform Vaccine Design

PROJECT SUMMARY Kaposi sarcoma-associated herpesvirus (KSHV) is an oncogenic virus that causes Kaposi sarcoma (KS), one of the most common malignancies in people living with HIV worldwide. KSHV also causes primary effusion lymphoma (PEL) and multicentric Castleman disease (KSHV-MCD). Infection is common in sub-Saharan Africa and often occurs early in childhood, while in the western hemisphere, infection is rare in the general population but more frequent in men who have sex with men. A vaccine that prevents KSHV infection and/or associated morbidity and mortality represents a critical unmet need. However, the types of immune responses a vaccine would need to elicit have not been well defined. Here we will seek to identify the relevant antigenic targets and specific epitopes targeted by KSHV-neutralizing antibodies and to establish the ability of neutralizing antibodies to protect against KSHV infection in a small animal model. To do this, we will leverage a large pre-collected repository of serum and PBMC samples from KSHV+ participants with and without KS disease to characterize the neutralizing antibody response to KSHV. We will produce recombinant KSHV glycoproteins that will be used to deplete serum binding antibodies and assess their contribution to the polyclonal serum neutralizing response. In parallel, we will isolate neutralizing monoclonal antibodies from KSHV+ PBMC samples and carry out in-depth structure-function analyses to identify critical sites of vulnerability on KSHV glycoproteins. Lastly, we will evaluate the ability of neutralizing KSHV monoclonal antibodies to prevent infection in a humanized mouse model of KSHV infection. Our studies will define the relevant antigens and epitopes targeted by neutralizing antibodies that arise from natural KSHV infection and thus inform the design and development of KSHV vaccines. Moreover in vivo protection from KSHV infection will establish critical proof of concept that a KSHV vaccine should seek to elicit neutralizing antibodies.