Project 3

项目3

• 批准号: 10598773
• 负责人: For Yue Tso
• 金额: $ 19.77万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10598773
• 关键词: AIDS related cancer; Acquired Immunodeficiency Syndrome; Address; Adherence; Adult; Affect; Africa; Africa South of the Sahara; Aftercare; Animal Model; Autopsy; Cells; Cohort Studies; Collaborations; Country; Coupled; Development; Disease; Drug resistance; Etiology; Future; HIV; HIV Infections; HIV-1; Herpesviridae; Herpesviridae Infections; High Prevalence; Histologic; Hospitals; Human; Human Herpesvirus 8; Human body; Immune system; Incidence; Individual; Infection; Kaposi Sarcoma; Lesion; Life; Location; Lytic; Malignant Neoplasms; Morbidity - disease rate; Oceans; Pathology; Patients; Persons; Plasma; Radiation therapy; Recurrence; Research; Research Institute; Research Personnel; Risk; Sampling; Seroprevalences; Site; Tanzania; Teaching Hospitals; Tissues; Treatment Failure; Uganda; Universities; Viral Load result; Virus; Zambia; antiretroviral therapy; brain tissue; cell transformation; cell type; co-infection; lytic gene expression; mortality; neoplastic cell; novel; peripheral blood; programs; reconstitution; seropositive; social; therapy design; transforming virus; viral DNA; viral RNA

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.

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）的HIV-1（PLWH）感染者。艾滋病相关的KS通常具有高侵袭性， 抑制性抗逆转录病毒治疗和化疗/放疗后的复发率。卡波西肉瘤- 相关疱疹病毒（KSHV）是与KS相关的病原体。KSHV的高流行率 和HIV-1使撒哈拉以南非洲数百万人在其一生中患KS的风险增加。类似于其他 疱疹病毒，KSHV可以保持潜伏与未检测到的病毒载量，但感染的个人可以是病毒血症 周期性地，表明存在一个或多个隐藏KSHV的未知储层 抑制治疗后出现感染或转化的细胞和病毒，导致KS。我们的团队已被 先前的研究表明，KSHV可以在脑组织中找到。缺乏合适的动物模型， 从KSHV感染者身上系统地采集各种组织样本， 来定位人体内的KSHV病毒库。然而，随着我们最近建立的能力，全身 通过对SSA尸检供体的尸检，我们现在可以评估KSHV储库的存在与否 在KSHV感染者的整个人体中。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库，并确定HIV-1感染的影响 和KS对这些储层的大小和分布的影响。我们假设，KSHV水库可以发现， 多个组织部位，并且HIV-1感染者的储库大小和分布将增加 KS患者。我们将通过以下具体目标来实现我们的主要目标：1）确定 KSHV组织库，并确定组织库的大小和宽度，在这两个 无症状和有症状的KS伴或不伴HIV合并感染。2)确定KSHV感染的细胞类型 并确定HIV-1感染和有症状的KS是否影响KSHV感染的大小和分布 细胞类型和KSHV细胞库的潜伏/裂解表达。这项研究意义重大，因为我们 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。这项研究的结果可能有助于我们了解KS复发 并确定任何未来新治疗/疗法的潜在目标位置， 特别是消除KSHV感染和KS发展。