Kaposi sarcoma-associated herpesvirus infection in HIV patients: potential role of HIV-associated extracellular vesicles

Abstract Kaposi sarcoma-associated herpesvirus (KSHV) is the causal agent for Kaposi sarcoma (KS), the most common malignancy in people living with HIV/AIDS. The oral cavity is a major route for KSHV infection and transmission. However, how KSHV breaches the oral epithelial barrier for spreading to the body is not clear. Here we show that extracellular vesicles (EVs) purified from saliva of HIV-positive individuals and secreted by HIV-1-infected T cells promote KSHV infectivity in both monolayer and 3-dimensional models of immortalized and primary human oral epithelial cells, establishing the latency of the virus. The HIV trans-activation response (TAR) element RNA in HIV-associated EVs contributes to the infectivity of KSHV through the epidermal growth factor receptor (EGFR). Cetuximab, a monoclonal neutralizing antibody to EGFR, blocks HIV-associated EV-enhanced KSHV infection. Our findings reveal that saliva containing HIV-associated EVs is a risk factor for enhancement of KSHV infection and that inhibition of EGFR serves as a novel strategy for controlling KSHV infection and transmission in the oral cavity. Author summary Kaposi sarcoma-associated herpesvirus (KSHV) is a causal agent for Kaposi sarcoma (KS), the most common malignancy in HIV/AIDS patients. Oral transmission through saliva is considered the most common route for spreading of the virus among HIV/AIDS patients. However, the role of HIV-specific components in co-transfection of KSHV is unclear. We demonstrate that extracellular vesicles (EV) purified from saliva of HIV patients and secreted by HIV-infected T cells promote KSHV infectivity in immortalized and primary oral epithelial cells. HIV-associated EVs promote KSHV infection depends on the HIV trans-activation element (TAR) RNA and EGFR of oral epithelial cells, both can be targeted for reducing KSHV infection. These results reveal that HIV-EVs is a risk factor for KSHV co-infection in the HIV-infected population.