HIV-associated exosomes promote infection of Kaposi sarcoma-associated herpesvirus via epidermal growth factor receptor.

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 exosomes purified from either the saliva of HIV-positive individuals or culture supernatants of HIV-1-infected T cell lines promote KSHV infectivity in immortalized and primary human oral epithelial cells. HIV-associated saliva exosomes contain the HIV trans-activation response (TAR) element, Tat, and Nef RNAs, but do not express Tat and Nef proteins. The TAR RNA in HIV-associated exosomes contributes to enhancing KSHV infectivity through the epidermal growth factor receptor (EGFR). An inhibitory aptamer to TAR RNA reduces KSHV infection facilitated by the synthetic TAR RNA in oral epithelial cells. Cetuximab, a monoclonal neutralizing antibody to EGFR, blocks HIV-associated exosome-enhanced KSHV infection. Our findings reveal that the saliva containing HIV-associated exosomes is a risk factor for the enhancement of KSHV infection and that the inhibition of EGFR serves as a novel strategy for preventing KSHV infection and transmission in the oral cavity.ImportanceKaposi 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 the virus among HIV/AIDS patients. However, the role of HIV-specific components in the co-transfection of KSHV is unclear. We demonstrate that exosomes purified from the saliva of HIV patients and secreted by HIV-infected T cell lines promote KSHV infectivity in immortalized and primary oral epithelial cells. HIV-associated exosomes promote KSHV infection depending on the HIV trans-activation element (TAR) RNA and EGFR of oral epithelial cells, which can be targeted for reducing KSHV infection. These results reveal that HIV-associated exosomes are a risk factor for KSHV infection in the HIV-infected population.