Models for KHSV transmission and its inhibition

KHSV 传播及其抑制模型

• 批准号: 10159872
• 负责人: John T West
• 金额: $ 41.66万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10159872
• 关键词: Address; Adult; Africa South of the Sahara; African; Anti-Retroviral Agents; Antibodies; Antibody Formation; Archives; B-Lymphocytes; BLT mice; Biological; Blood; Cell Separation; Cells; Complementary DNA; Country; Development; Disease; Epithelium; Etiology; Exposure to; Foundations; HIV Infections; HIV Seronegativity; HIV-1; Helminths; 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; 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.

抽象的 卡波西肉瘤（KS）是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 中发病率增加 尽管抗逆转录病毒（ART）抑制了 HIV-1 病毒载量，但仍感染了患者。它也作为 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，我们已经证明 KSHV 感染是获得性的 HIV-1 感染主要发生在儿童早期，是一个主要危险因素，并且粘膜暴露 传染性唾液是可能的传播机制。最近，我们从赞比亚和 坦桑尼亚证明高滴度中和抗体反应 (nAb) 主要在个体中产生 有症状的 KS 患者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 不能预防长期慢性感染后的疾病。然而，预防能力 HIV-1/SIV 感染挑战模型中已证实被动施用广泛的 nAb； 然而，预先存在的 nAb 阻止 KSHV 传播的能力尚未经过测试。此外，虽然 体外 KSHV 进入过程已得到一定深入的研究，精确的病毒和细胞相互作用 KSHV 在组织水平上的参与，尚未明确阐明。在某种程度上，这种知识差距 这是由于缺乏人类 KSHV 传播的体内模型造成的。拟建项目适用 我们团队在 KS、KSHV、人类 KSHV 抗体反应和 KSHV 感染方面的长期经验 我们开发的人性化小鼠模型，旨在解决 KSHV 造成的知识差距 传播和传播。我们的总体目标是确定可以的免疫反应 防止 KSHV 感染和传播，从而预防 KS。我们的假设是 KSHV nAb 可在离体人体器官组织模型中预防 KSHV 传播 以及 KSHV 感染的人源化小鼠模型。该假设将通过 3 个具体目标进行检验： 1) 开发器官型口腔和阴道上皮培养模型以了解 KSHV 传播 动力学并测试高 nAb 滴度的血清是否可以预防跨上皮 KSHV 感染； 2）测试 KSHV nAb 在粘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，以及 3) 人单克隆 KSHV nAb 的分离和 表征它们对 KSHV 传播的影响。该项目将阐明以下机制： KSHV 传播和传播，并为开发疫苗战略奠定基础 预防 KSHV 感染。最终，此类研究将扩大我们预防 KSHV 感染的能力 及相关肿瘤。