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（Kaposi）的肉瘤（KS）是撒哈拉以南非洲高度普遍的恶性肿瘤。这个癌症，有 Kaposi的肉瘤疱疹病毒（KSHV）作为病因，在HIV-1的发病率增加 尽管抗逆转录病毒（ART）抑制HIV-1病毒载量，但受感染的患者。它也作为一个 HIV阴性人群中的侵袭性肿瘤。我们的团队一直在研究KS和KSHV KS流行国家的传播，我们已经表明KSHV感染已获得 HIV-1感染主要是在幼儿期，是主要危险因素，并且粘膜暴露于 传染性唾液是传播的可能机制。最近，我们来自赞比亚和 坦桑尼亚表明，高滴度中和中和AB反应（NAB）主要在个体中发展 与有症状的KS相对于感染无症状的个体，这表明NAB不是 KS保护的关联。因此，就像在HIV-1病毒宿主相互作用中一样，KSHV似乎 长期慢性感染后NAB无法预防疾病。但是，预防能力 在HIV-1/SIV感染性挑战模型中已证明了被动管理的NAB。 鉴于，未经测试的NAB预防KSHV传输的能力。另外，而 已经对体外KSHV进入过程进行了一些深度，即精确的病毒和细胞相互作用 在组织水平上参与KSHV，尚未清楚地阐明。在某种程度上，这个知识差距 由于缺乏人类KSHV传播的体内模型而导致的结果。拟议的项目适用 我们团队在KS，KSHV，Human KSHV AB的反应和KSHV感染中的长期经验 我们开发的人源化小鼠模型，以解决KSHV构成的知识差距 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，从而防止KS。我们的假设是 KSHV NAB可以防止在体内人体器官组织模型中进行KSHV传播 以及在人源化的KSHV感染的小鼠模型中。该假设将以3个特定目的进行检验： 1）开发器官口服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防止跨上皮KSHV感染； 2）测试 KSHV NAB是否在人源化的粘膜和血液暴露模型中具有保护性， KHSV的感染和传播，3）分离人类单克隆KSHV NAB和 表征它们对KSHV传输的影响。该项目将阐明 KSHV传播和传播，并为开发疫苗开发疫苗的策略奠定了基础 防止KSHV感染。最终，此类研究将扩大我们防止KSHV感染的能力 和相关的肿瘤。