Project 3

摘要 卡波西肉瘤(KS)是一种与HIV/AIDS相关的恶性肿瘤，是人类最常见的癌症之一 撒哈拉以南非洲(SSA)艾滋病毒携带者(PLWH)。与艾滋病相关的KS通常具有侵袭性，具有高 尽管进行了抑制性抗逆转录病毒治疗和化疗/放射治疗，复发率仍然很高。卡波西肉瘤- 相关疱疹病毒(KSHV)是与KS相关的病原体。两种KSHV的高流行率 HIV-1使数百万生活在SSA的人在一生中患KS的风险增加。与其他类似 疱疹病毒，KSHV可以在未检测到病毒载量的情况下保持潜伏，但受感染的人可能是病毒携带者 周期性地，暗示存在一个或多个未知的水库，这些水库正在窝藏KSHV 感染或转化的细胞和病毒在抑制治疗后出现，导致KS。我们队有 此前有研究表明，KSHV可在脑组织中发现。缺乏合适的动物模型和不能 对KSHV感染者的各种组织隔间进行系统采样阻碍了这一探索 以确定这些KSHV病毒在人类体内的储存库。然而，随着我们最近建立的全身能力 在SSA的尸检中，我们现在可以评估KSHV蓄水池的存在或不存在 遍及整个人体内的KSHV感染者。我们的总体目标是确定KSHV KSHV血清阳性个体的组织和细胞储存库，并确定HIV-1感染的影响 和KS对这些储层的规模和分布的影响。我们假设KSHV水库可以在 多个组织部位，在HIV-1感染者中，储存库的大小和分布将增加 和KS患者。我们将通过以下具体目标实现我们的主要目标：1)确定 KSHV组织储集层，并确定两个地区组织储集层的大小和宽度 无症状和有症状的KS合并或不合并HIV感染。2)鉴定KSHV感染的细胞类型 并确定HIV-1感染和症状性KS是否影响感染KSHV的大小和分布 KSHV细胞库的细胞类型和潜伏/裂解表达。这项拟议的研究具有重要意义，因为我们 有独特的机会利用我们在赞比亚的全身尸检能力来解决尚未解决的问题 回答了是否存在KSHV组织储存库、涉及的细胞类型以及HIV-1如何 KS的感染和发展将影响这些水库，同时将这种能力扩大到我们的 坦桑尼亚的其他SSA合作伙伴。这项研究的发现可能有助于我们对KS复发的理解 在治疗后，并确定任何未来的新治疗/治疗的潜在目标位置， 具体消除KSHV感染和KS发展。

ABSTRACT Kaposi sarcoma (KS), an HIV/AIDS-associated malignancy, is one of the most prevalent cancers in people living with HIV-1 (PLWH) in sub-Saharan Africa (SSA). AIDS-associated KS is often aggressive with a high rate of recurrence despite suppressive antiretroviral therapy and chemo/radiotherapy. Kaposi sarcoma- associated herpesvirus (KSHV) is the etiologic agent associated with KS. The high prevalence of both KSHV and HIV-1 put millions of people in SSA at an increased risk of developing KS in their lifetime. Similar to other herpesviruses, KSHV can remain latent with undetected viral load, but infected individuals can be viremic periodically, suggesting the presence of an unknown reservoir or reservoirs that are harboring the KSHV infected or transformed cells and virus emerged after suppressive treatment to lead to KS. Our team has previously shown that KSHV can be found in brain tissues. The lack of a suitable animal model and the inability to systematically sample various tissue compartments from KSHV infected individuals have hindered the quest to locate these KSHV reservoirs in humans. However, with our recently established capability of full-body autopsies on postmortem donors in SSA, we can now assess the presence or absence of KSHV reservoirs throughout the entire human body in KSHV infected individuals. Our overall objective is to identify the KSHV tissue and cellular reservoirs in KSHV seropositive individuals, and to determine the effects of HIV-1 infection and KS on the size and distribution of these reservoirs. We hypothesize that KSHV reservoirs can be found in multiple tissue sites, and the size and distribution of the reservoirs will increase in HIV-1 infected individuals and KS patients. We will accomplish our main objective through the following specific aims: 1) Identify the KSHV tissue reservoirs and determine the magnitude and breadth of the tissue reservoirs in both asymptomatic and symptomatic KS with or without HIV co-infection. 2) Identify the KSHV infected cell types and determine whether HIV-1 infection and symptomatic KS affect the size and distribution of KSHV infected cell types and latency/lytic expression of the KSHV cellular reservoirs. This proposed study is significant as we have the unique opportunity to utilize our full-body autopsy capability in Zambia to address the yet-to-be answered questions of whether there are KSHV tissue reservoirs, the cell types involved, and how HIV-1 infection and development of KS will impact these reservoirs, and simultaneously expand this capability to our other SSA partner in Tanzania. Findings from this study may contribute to our understanding of KS recurrence after treatment and identify the potential target locations for any future novel treatment/therapy that can specifically eliminate KSHV infection and KS development.