Identification of the Kaposi\u27s Sarcoma-associated Herpesvirus (KSHV) Surface Glycoprotein Targets of Human KSHV-specific Neutralizing Antibody Responses

Kaposi’s sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV-8), is the etiological agent of Kaposi’s sarcoma (KS), and is also associated with two B cell malignancies, primary effusion lymphoma and multicentric Castleman\u27s disease. The distribution of KSHV varies globally with high prevalence in some areas of sub-Saharan Africa (SSA), where seroprevalence can be as high as 80%. It is estimated that nearly 44,000 new cases of KS emerge annually globally, with the highest incidents occurring in Africa, where KSHV is endemic. Currently, there is no prophylactic vaccine against KSHV, and efforts to develop prophylactic vaccines have been limited. Elicitation of neutralizing antibodies (nAbs) often correlates with protection during viral infections in humans, but it is not clear whether nAbs against KSHV will also convey protection against infection. KSHV initiates infection via interaction with various receptors on the surface of target cells, which is primarily mediated by multiple viral glycoproteins embedded in the viral envelope. These glycoproteins play important roles in virion attachment and entry into target cells, therefore they could be potential targets for KSHV-specific nAbs.Characterization of the human neutralizing antibody responses against KSHV envelope glycoproteins and identifying the targets of these antibodies, are needed for designing an effective vaccine against KSHV. KSHV virions incorporate eight glycoproteins into their envelope: ORF8 (gB), ORF28, ORF68, ORF22 (gH), ORF47 (gL), ORF39 (gM), ORF53 (gN) and gpK8.1. Through testing the ability of each KSHV glycoprotein in recognizing/adsorbing KSHV-specific nAbs by this study, it was determined that multiple KSHV glycoproteins were able to bind to these antibodies in a majority of KSHV infected individuals. In addition, the ability of each KSHV glycoprotein in depleting the KSHV nAbs from KSHV positive plasma varied among individuals. Among all the KSHV envelope glycoproteins, gH/gL complex showed high adsorption/recognition levels of KSHV-specific nAbs in 80% of the participants analyzed. These findings suggest that nAbs responses are variable in KSHV infected individuals, and multiple KSHV envelope glycoproteins are the targets of KSHV-specific nAbs, with gH/gL complex being the most predominant target, which can serve as a potential target antigen for developing prophylactic vaccines against KSHV. Advisor: Charles Woo