Models for KHSV transmission and its inhibition

KHSV 传播及其抑制模型

• 批准号: 9765885
• 负责人: John T West
• 金额: $ 43.86万
• 依托单位: UNIVERSITY OF NEBRASKA LINCOLN
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-09 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9765885
• 关键词: Address; Adult; Africa South of the Sahara; African; Anti-Retroviral Agents; Antibodies; Antibody Formation; Archives; B-Lymphocytes; BLT mice; Biological; Blood; Cells; Complementary DNA; Country; Development; Disease; Epithelial; Etiology; Exposure to; Foundations; HIV Infections; HIV Seronegativity; HIV-1; Helminths; Herpesviridae; Herpesviridae Infections; Human; Human Herpesvirus 8; Immune response; Immunoglobulins; In Vitro; Incidence; Individual; Infection; Infection prevention; Insecta; Intravenous; Investigation; Kaposi Sarcoma; Knowledge; Ligands; Malaria; Malignant Neoplasms; Modeling; Mucous Membrane; Neoplasms; Oral; Palate Kaposi' s Sarcoma; Parasitic infection; Patients; Population; Prevalence; Prevention; Prevention strategy; Process; Reagent; Reporting; Research; Risk Factors; Role; Route; SIV; Saliva; Serum; Sexual Transmission; Source; Structure; System; Tanzania; Testing; Tissue Model; Tissues; Vaccines; Vagina; Viral; Viral Load result; Zambia; cell type; cervicovaginal; chronic infection; early childhood; experience; human model; human monoclonal antibodies; human tissue; humanized mouse; in vivo Model; intraperitoneal; mouse model; neutralizing antibody; novel; prevent; prophylactic; protective efficacy; transmission process; tumor; vaccine development; vaginal mucosa; virus host interaction

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 neutralizing Ab responses (nAb) develop primarily in individuals with 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 of 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.

摘要 卡波西肉瘤(KS)是一种在撒哈拉以南非洲地区高度流行的恶性肿瘤。这种癌症，与 卡波西肉瘤疱疹病毒(KSHV)作为病原体在HIV-1中的发病率呈上升趋势 尽管抗逆转录病毒(ART)抑制了HIV-1病毒载量，但仍有患者受到感染。它也作为一种 HIV阴性人群中的侵袭性肿瘤。我们团队一直在研究KS和KSHV 在KS流行国家传播，我们已经表明KSHV感染是获得性的 主要是在儿童早期，艾滋病毒-1感染是一个主要的危险因素，而粘膜接触到 传染性唾液可能是传播的机制。最近，我们来自赞比亚和赞比亚的结果 坦桑尼亚证明，高滴度中和抗体反应(NAB)主要发生在个人身上 有症状的KS与感染的无症状个体相反，这表明NAB不是一种 KS保护的相关性。因此，就像HIV-1病毒与宿主的相互作用一样，KSHV似乎 NAB在长期慢性感染后不能预防疾病。然而，疫苗的预防能力 被动广泛应用NAB已在HIV-1/SIV感染挑战模型中得到证实； 然而，预先存在的NAB防止KSHV传播的能力尚未得到测试。此外，虽然 在体外，KSHV的进入过程已经有了一定的深入研究，精确的病毒与细胞的相互作用 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，这种知识差距 这是由于缺乏人体内传播KSHV的模型所致。建议的项目适用于 我们团队在KS、KSHV、人KSHV抗体应答和KSHV感染方面的长期经验 我们开发的人性化小鼠模型，以解决KSHV带来的知识鸿沟 传播和传播。我们的总体目标是确定免疫反应(S)，可以 预防KSHV感染和传播，从而预防KS。我们的假设是 KSHV NAB在体外人体器官组织模型中对KSHV传播的保护作用 在KSHV感染的人源化小鼠模型中。这一假设将通过三个具体目标进行检验： 1)建立器官型口腔和阴道上皮培养模型以了解KSHV的传播 检测高滴度NAB血清能否预防KSHV跨上皮性感染；2)检测 KSHV NAB在黏膜和血液暴露的人源化BLT小鼠模型中是否具有保护作用， KHSV的感染和传播；3)人源单抗KSHV NAB和 它们对KSHV传播的影响的特征。该项目将阐明 KSHV的传播和传播，并为制定疫苗战略奠定基础 预防KSHV感染。最终，这些研究将扩大我们预防KSHV感染的能力。 以及相关的肿瘤。