Use of a non-human primate model to define the role of T cell immune responses in persistent Kaposi sarcoma-associated herpesvirus infection and Kaposi sarcoma pathogenesis

项目摘要 卡波西肉瘤相关疱疹病毒（KSHV）是几种人类恶性肿瘤的病原体，包括 卡波西肉瘤（KS）。KS是最常见的KSHV相关恶性肿瘤，报告了> 44，000例新病例 每年在全球范围内。最易感染KSHV/KS的人群是免疫功能低下的个体， 感染艾滋病病毒的人。艾滋病毒/艾滋病感染者患KS的风险高于 艾滋病毒阴性个体。适应性T细胞免疫应答，特别是CD 4+和CD 8 + T细胞，已经被广泛应用。 显示在KSHV感染和随后的KS发病机制中起关键作用。虽然， 已观察到CD 4+和CD 8 + T细胞水平与KS发展，但尚未发现这种关系。 由于缺乏合适的动物模型，最近的发展共同的 绒猴（Callithrix jacchus）作为对KSHV感染易感的非人灵长类动物（NHP）模型， 能够在免疫抑制下发展KS样病变开辟了新的领域， 免疫细胞在KS发展中的作用。因此，我们的目标是确定减少的CD 4+和 在绒猴NHP模型中持续KSHV感染和随后KS发病机制中的CD 8 + T细胞水平 抗-CD 4和抗-CD 8单克隆抗体（mAb）已用于耗尽T细胞并诱导T细胞凋亡。 在小鼠和NHP动物模型中的免疫抑制，使得能够研究CD 4 +/CD 8 + T细胞在控制 几种病毒的复制。为了避免在给药时对鼠mAb产生任何不良反应， 我们将嵌合（鼠-绒猴）抗CD 4/CD 8单克隆抗体，并表征其生化和 在体外和小鼠体内的药代动力学特性，然后我们将确定抗体介导的T细胞 对各种免疫细胞群体的消耗（目的1）。然后我们将挑战免疫抑制的绒猴 与KSHV.219病毒感染，并确定抗体介导的CD 4+和/或CD 8 + T细胞耗竭的程度， 细胞使KSHV持续感染和KS发病机制免疫受损的绒猴（目的2）。的 本计画的成功完成将验证普通绒猴作为了解病因的工具 揭示了CD 4+和/或CD 8 + T细胞耗竭在持续性KSHV中的关键作用 感染和随后KS发病机制。

PROJECT ABSTRACT Kaposi sarcoma-associated herpesvirus (KSHV) is the causative agent of several human malignancies including Kaposi sarcoma (KS). KS is the most common KSHV-associated malignancy, with >44,000 new cases reported worldwide each year. The population most vulnerable to KSHV/KS are immunocompromised individuals such as people infected with HIV. Individuals with HIV/AIDS have a higher risk of developing KS when compared to HIV-negative individuals. The adaptive T cell immune response, especially CD4+ and CD8+ T cells, has been shown to play a crucial role in KSHV infection and subsequent KS pathogenesis. Although correlations between CD4+ and CD8+ T cell levels and KS development have been observed, this relationship has not been experimentally validated due to the lack of a suitable animal model. The recent development of the common marmoset (Callithrix jacchus) as a non-human primate (NHP) model that is susceptible to KSHV infection and capable of developing KS-like lesions under immunosuppression opens new frontiers to experimentally validate the role immune cells play in KS development. Thus, our objective is to define the role of reduced CD4+ and CD8+ T cell levels in persistent KSHV infection and subsequent KS pathogenesis in the marmoset NHP model. Anti-CD4 and anti-CD8 monoclonal antibodies (mAbs) have been used to deplete T cells and induce immunosuppression in both murine and NHP animal models, enabling study of CD4+/CD8+ T cells in controlling replication of several viruses. To avoid any adverse responses to murine mAbs when administered into marmosets, we will chimerize (murine-marmoset) anti-CD4/CD8 mAbs and characterize their biochemical and pharmacokinetic properties in vitro and in mice, then we will determine the effects of antibody-mediated T cell depletion on various immune cell populations (Aim 1). We will then challenge immunosuppressed marmosets with KSHV.219 virus and determine the extent to which antibody-mediated depletion of CD4+ and/or CD8+ T cells enables persistent KSHV infection and KS pathogenesis in immunocompromised marmosets (Aim 2). The successful completion of this project will validate the common marmoset as a tool for understanding the etiology of KS and uncover the critical role that CD4+ and/or CD8+ T cell depletion plays in allowing persistent KSHV infection and subsequent KS pathogenesis in immunocompromised animals.