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 trans-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.IMPORTANCE 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 trans-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.

中文翻译：

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人类免疫缺陷病毒相关外来体通过表皮生长因子受体促进卡波西氏肉瘤相关疱疹病毒感染。

卡波西氏肉瘤相关疱疹病毒（KSHV）是卡波西氏肉瘤（KS）的病原体，卡波西氏肉瘤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。但是，尚不清楚KSHV怎样突破口腔上皮屏障传播到人体。在这里，我们表明，从HIV阳性个体的唾液或HIV-1感染的T细胞系的培养上清液中纯化的外泌体，在永生化的和人类原始口腔上皮细胞中促进了KSHV感染性。与HIV相关的唾液外泌体包含HIV反式激活应答元件（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）有助于增强KSHV感染性。针对TAR RNA的抑制性适体可减少口腔上皮细胞中合成TAR RNA促进的KSHV感染。西妥昔单抗是一种针对EGFR的单克隆中和抗体，可阻断HIV相关的外泌体增强的KSHV感染。我们的发现表明，唾液中含有与HIV相关的外泌体是导致KSHV感染增强的危险因素，而抑制EGFR是预防KSHV感染和在口腔中传播的一种新策略。重要Kaposi肉瘤相关疱疹病毒（KSHV） ）是卡波西肉瘤（KS）的病因，卡波西肉瘤（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在HIV / AIDS患者中传播病毒的最常见途径。但是，尚不清楚HIV特异性成分在KSHV的共转染中的作用。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在永生化和原代口腔上皮细胞中促进KSHV感染性。与HIV相关的外泌体促进了KSHV感染，这取决于口腔上皮细胞的HIV反式激活应答元件（TAR）RNA和EGFR，可以靶向减少KSHV感染。这些结果表明，与HIV相关的外泌体是感染HIV的人群中KSHV感染的危险因素。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在永生化和原代口腔上皮细胞中促进KSHV感染性。与HIV相关的外泌体可促进KSHV感染，这取决于口腔上皮细胞的HIV反式激活应答元件（TAR）RNA和EGFR，可以靶向减少KSHV感染。这些结果表明，与HIV相关的外泌体是感染HIV的人群中KSHV感染的危险因素。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在永生化和原代口腔上皮细胞中促进KSHV感染性。与HIV相关的外泌体促进了KSHV感染，这取决于口腔上皮细胞的HIV反式激活应答元件（TAR）RNA和EGFR，可以靶向减少KSHV感染。这些结果表明，与HIV相关的外泌体是感染HIV的人群中KSHV感染的危险因素。可以减少KSHV感染。这些结果表明，与HIV相关的外泌体是感染HIV的人群中KSHV感染的危险因素。可以减少KSHV感染。这些结果表明，与HIV相关的外泌体是感染HIV的人群中KSHV感染的危险因素。