Models for KHSV transmission and its inhibition

KHSV 传播及其抑制模型

• 批准号: 10527645
• 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/10527645
• 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 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 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.

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， 以Kaposi的肉瘤疱疹病毒（KSHV）为病因，发病率的发病率增加 尽管抗逆转录病毒（ART）抑制HIV-1病毒载量，但HIV-1感染了患者。也是如此 在HIV阴性人群中是侵略性肿瘤。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 HIV-1感染主要在幼儿期获得，是主要的危险因素，并且 粘膜暴露于感染性唾液中是传播的可能机制。最近， 我们来自赞比亚和坦桑尼亚的结果表明，高滴水neutwith有症状的KS 反对感染无症状的个体，表明NAB与KS不相关 保护。因此，就像在HIV-1病毒宿主相互作用中一样，KSHV NAB似乎无法 长期慢性感染后预防疾病。但是，预防能力诺言 AB响应（NAB）主要在被动管理的个体中发展 在HIV-1/SIV感染挑战模型中得到了证明；而预先的能力 现有的NAB预防KSHV传输未经测试。另外，体外KSHV 进入过程已经深入研究了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。部分知识 差距是由于缺乏人体KSHV传播的体内模型而引起的。提议 项目运用我们团队在KS，KSHV，Human KSHV AB回应的长期经验， 和KSHV感染 我们开发的人源化鼠标模型，以解决由 KSHV传播和传播。我们的总体目标是确定免疫反应 可以防止KSHV感染和传播，从而防止KS。我们的 假设是kshv nab可以保护外体内的KSHV传播 在KSHV感染的人性化小鼠模型中，器官型组织模型。假设 将以3个特定目的进行测试：1）开发器官口服和阴道上皮培养 了解KSHV传输动力学并测试具有高NAB滴度的血清的模型 防止跨上皮KSHV感染； 2）测试KSHV NAB是否在人源化中具有保护性 粘膜和血液暴露，KHSV的感染和传播的BLT小鼠模型以及3） 人类单克隆KSHV NAB的隔离及其对KSHV的影响的表征 传播。该项目将阐明KSHV传播和传播的机制， 并为开发疫苗以防止KSHV感染的策略奠定了基础。 最终，此类研究将扩大我们防止KSHV感染和相关的能力 肿瘤。