Department of Biological Sciences, Case Western Reserve University School of Dental Medicine, Cleveland, Ohio, USA.
Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
J Virol. 2020 Apr 16;94(9). doi: 10.1128/JVI.01782-19.
Kaposi's sarcoma-associated herpesvirus (KSHV) is the causal agent for Kaposi's sarcoma (KS), the most common malignancy in people living with human immunodeficiency virus (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 the 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 -activation response element (TAR), 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 against TAR RNA reduces KSHV infection facilitated by the synthetic TAR RNA in oral epithelial cells. Cetuximab, a monoclonal neutralizing antibody against EGFR, blocks HIV-associated exosome-enhanced KSHV infection. Our findings reveal that 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. Kaposi's sarcoma-associated herpesvirus (KSHV) is the causal agent for Kaposi's 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 cotransfection of KSHV is unclear. We demonstrate that exosomes purified from the saliva of HIV-positive 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, which depends on HIV -activation response 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.
卡波氏肉瘤相关疱疹病毒（KSHV）是卡波氏肉瘤（KS）的病原体，KS 是人类免疫缺陷病毒（HIV）/艾滋病患者中最常见的恶性肿瘤。口腔是 KSHV 感染和传播的主要途径。然而，KSHV 如何突破口腔上皮屏障传播到全身尚不清楚。在这里，我们发现从 HIV 阳性个体的唾液中或从 HIV-1 感染的 T 细胞系的培养上清液中纯化的外泌体促进了永生化和原代人口腔上皮细胞中的 KSHV 感染力。HIV 相关的唾液外泌体包含 HIV-激活反应元件（TAR）、Tat 和 Nef RNA，但不表达 Tat 和 Nef 蛋白。HIV 相关外泌体中的 TAR RNA 通过表皮生长因子受体（EGFR）促进 KSHV 感染力。针对 TAR RNA 的抑制性适体减少了口腔上皮细胞中合成 TAR RNA 促进的 KSHV 感染。针对 EGFR 的单克隆中和抗体西妥昔单抗阻断了 HIV 相关外泌体增强的 KSHV 感染。我们的研究结果表明，含有 HIV 相关外泌体的唾液是增强 KSHV 感染的危险因素，抑制 EGFR 可作为预防口腔中 KSHV 感染和传播的新策略。卡波氏肉瘤相关疱疹病毒（KSHV）是卡波氏肉瘤（KS）的病原体，KS 是 HIV/AIDS 患者中最常见的恶性肿瘤。通过唾液的口腔传播被认为是 HIV/AIDS 患者中病毒传播最常见的途径。然而，HIV 特异性成分在 KSHV 的共转染中的作用尚不清楚。我们证明，从 HIV 阳性患者的唾液中纯化并由 HIV 感染的 T 细胞系分泌的外泌体促进了永生化和原代口腔上皮细胞中的 KSHV 感染力。HIV 相关的外泌体促进 KSHV 感染，这取决于口腔上皮细胞的 HIV-激活反应元件（TAR）RNA 和 EGFR，可针对这些靶点减少 KSHV 感染。这些结果表明，HIV 相关的外泌体是 HIV 感染人群中 KSHV 感染的一个危险因素。
