Neutralizing and FcR-mediating antibody specificities and function in control of HHV-8 infection

About This Grant

PROJECT SUMMARY/ABSTRACT Kaposi’s Sarcoma (KS), driven by Kaposi’s Sarcoma-associated Herpesvirus (KSHV), remains a leading AIDS- associated malignancy and a growing concern among immunocompromised populations, including people living with HIV (PLWH) and solid organ transplant recipients. Despite effective antiretroviral therapy (ART), KS can still emerge in individuals with suppressed HIV viral loads and preserved CD4+ T cell counts, underscoring an unmet critical need for immune interventions beyond ART and T cell-mediated control. One promising strategy involves harnessing antibodies capable of recruiting effector cells to eliminate infected cells. Results from preclinical vaccine studies and clinical trials indicate that Fc-mediated effector function of antibodies significantly contribute to overall antibody efficacy in treatment and prevention of numerous carcinogenic viral infections. However, there remains a gap in our knowledge regarding the role of antibodies with Fc-mediated effector functions in controlling KSHV in immunocompromised population. This proposal will leverage the rhesus macaque rhadinovirus (RRV)/rhesus macaque (RM) model, which closely mimics KSHV infection, to investigate the capacity of antibodies with Fc-mediated functions to recruit effector cells and suppress RRV reactivation following SIV co- infection. Specifically, we will compare antibody responses during primary RRV infection and following RRV reactivation due to SIV co-infection; assess whether RRV reactivation drives B cell maturation capacity of producing Fc-functional antibodies; and evaluate the efficacy of these antibodies in immunocompromised animals to prevent RRV reactivation. Our central hypothesis is that KSHV-specific antibodies with Fc-mediated functions are critical for controlling KSHV infection, and their presence during immune suppression will prevent KSHV reactivation and KS development. Preliminary data supports this hypothesis, demonstrating that plasma from RRV-infected RMs contains antibodies both recognize infected cells and exhibit Fc-mediated effector functions. The scientific premise in this K01 is that characterizing RRV-specific antibodies capable of recruiting NK cells and monocytes will inform future KSHV immunotherapies for PLWH. At the completion of the proposed research, my expected outcomes are two-fold: 1) scientific achievements: understanding of KSHV-specific humoral responses in presence of HIV co-infection in NHP model; and 2) career development: to gain knowledge and skills for leading a preclinical and translational research program using NHP models to develop and test vaccines and immunoprophylaxis strategies in the field of AIDS-associated malignancies.