Models for KHSV transmission and its inhibition

摘要 卡波西肉瘤(KS)是一种在撒哈拉以南非洲非常常见的恶性肿瘤。这种癌症， 以卡波西肉瘤疱疹病毒(KSHV)为病原体，在我国发病率呈上升趋势。 尽管抗逆转录病毒(ART)抑制了HIV-1病毒载量，但仍有HIV-1感染患者。它还 在HIV阴性人群中以侵袭性肿瘤的形式发生。我们的团队一直在研究KS 和KSHV在KS流行国家的传播，我们已经表明KSHV感染是 艾滋病毒-1感染主要是在儿童早期获得的，是一个主要的危险因素， 粘膜接触感染性唾液可能是传播机制。最近， 我们在赞比亚和坦桑尼亚的结果表明，有症状的KS高滴度神经AS 与感染的无症状个体相反，这表明NAB与KS无关 保护。因此，就像在HIV-1病毒-宿主相互作用中一样，KSHV NAB似乎不能 预防长期慢性感染后的疾病。然而，预防复发的能力 AB反应(NAB)主要发生在被动给药广泛的个体中 已在HIV-1/SIV感染挑战模型中得到证明；而前病毒感染的能力 现有的防止KSHV传播的NAB未经测试。此外，虽然KSHV在体外 进入过程已经有了一些深入的研究，精确的病毒和细胞的相互作用 KSHV在组织水平上的参与，目前还没有明确的阐明。在某种程度上，这种知识 GAP是由于缺乏人体内传播KSHV的模型所致。建议数 该项目应用了我们团队在KS、KSHV、人KSHV抗体应答方面的长期经验， 和KSHV感染 我们开发的人性化老鼠模型，以解决由 KSHV的传播和传播。我们的总体目标是识别免疫反应(S) 可以预防KSHV的感染和传播，从而预防KS。我们的 假设KSHV NAB对KSHV在体外人的传播具有保护作用 器官组织模型和人源化KSHV感染小鼠模型。假说 将以3个具体目标进行测试：1)发展器官型口腔和阴道上皮培养 了解KSHV传播动力学和检测高NAB滴度血清的模型 防止跨上皮型KSHV感染；2)测试KSHV NAB在人源化的 BLT-小鼠粘膜和血液暴露、KHSV感染和传播的模型，以及3) 人源KSHV单抗NAB的分离及其对KSHV影响的研究 变速箱。该项目将阐明KSHV的传播和传播机制， 并为开发预防KSHV感染的疫苗的战略奠定了基础。 最终，这些研究将扩大我们预防KSHV感染和相关疾病的能力 肿瘤。

ABSTRACT Kaposi's sarcoma (KS) is a highly prevalent malignancy in sub-Saharan Africa. This cancer, with Kaposi's sarcoma herpesvirus (KSHV) as the etiologic agent, is at increased incidence in HIV-1 infected patients despite antiretroviral (ART) suppression of HIV-1 viral load. It also occurs as an aggressive tumor in the HIV-negative population. Our team has been studying KS and KSHV transmission in KS endemic countries and we have shown that KSHV infection is acquired predominantly in early childhood, HIV-1 infection is a major risk factor, and that mucosal exposure to infectious saliva is the likely mechanism of transmission. More recently, our results from Zambia and Tanzania demonstrated that high titer neutwith symptomatic KS as opposed to infected asymptomatic individuals, suggesting that nAb is not a correlate of KS protection. Thus, much like in the HIV-1 virus-host interaction, it appears that KSHV nAb cannot prevent disease after long-term chronic infection. However, the prophylactic capacity ofralizing Ab responses (nAb) develop primarily in individuals passively administered broadly nAb has been demonstrated in HIV-1/SIV infectious challenge models; whereas, the ability of pre- existing nAb to prevent KSHV transmission is untested. In addition, while the in vitro KSHV entry process has been studied in some depth, the precise viral and cellular interactions involved in KSHV at the tissue level, have not been clearly elucidated. In part, this knowledge gap results from the lack of an in vivo model of human KSHV transmission. The proposed project applies our team's long-term experience with KS, KSHV, human KSHV Ab responses, and KSHV infection in a humanized mouse model that we have developed, to address the knowledge gap posed by KSHV transmission and dissemination. Our overall objective is to identify immune response(s) that can protect against KSHV infection and transmission, and thereby, prevent KS. Our hypothesis is that KSHV nAb can be protective against KSHV transmission in ex vivo human organotypic tissue models and in a humanized mouse model of KSHV infection. The hypothesis will be tested with 3 specific aims: 1) Develop organotypic oral and vaginal epithelial culture models to understand KSHV transmission dynamics and to test whether sera with high nAb titer prevents trans-epithelial KSHV infection; 2) test whether KSHV nAb is protective in a humanized BLT-mouse model of mucosal and blood exposure, infection and dissemination of KHSV, and 3) isolation of human monoclonal KSHV nAb and characterization of their impact on KSHV transmission. This project will clarify the mechanisms of KSHV transmission and dissemination, and lay the foundations for strategies to develop a vaccine to prevent KSHV infection. Ultimately, such studies will expand our capacity to prevent KSHV infection and associated neoplasms.