Kaposi's sarcoma and human herpesvirus in Africa

非洲的卡波西肉瘤和人类疱疹病毒

• 批准号: 8334830
• 负责人: Charles Wood
• 金额: $ 59万
• 依托单位: UNIVERSITY OF NEBRASKA LINCOLN
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8334830
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Adult; Africa; Africa South of the Sahara; African; Age-Months; Anti-Retroviral Agents; Antibodies; CD4 Lymphocyte Count; Cellular Immunity; Centers for Disease Control and Prevention (U.S.); Child; Childhood; Collaborations; Country; Data; Development; Diagnosis; Disease; Disease Progression; Epidemic; Frequencies; Future; Goals; HIV; HIV-1; Herpesviridae; Horizontal Disease Transmission; Household; Human; Human Herpesvirus 8; Immune; Immune response; Immunosuppression; Incidence; Individual; Infant; Infection; Intervention; Kaposi Sarcoma; Laboratories; Lead; Literature; Malignant Neoplasms; Measures; Mothers; Participant; Pathogenesis; Patients; Perinatal; Populations at Risk; Positioning Attribute; Predisposition; Prevention Guidelines; Recovery; Recruitment Activity; Relative (related person); Reporting; Research Infrastructure; Risk; Risk Factors; Route; Saliva; Testing; Vertical Disease Transmission; Viral; Viral Load result; Virus; Zambia; cell mediated immune response; cohort; early childhood; high risk; in utero; neutralizing antibody; patient population; prevent; public health relevance; restoration; transmission process

DESCRIPTION (provided by applicant): Incidence of Kaposi's sarcoma (KS) - a devastating malignancy closely associated with HIV/AIDS - is still very wide-spread in sub-Saharan African countries such as Zambia, where anti-retroviral therapy (ARV) has only recently become available. Human herpesvirus-8 (HHV-8) or Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent associated with KS. Our laboratory is widely recognized for its study of the transmission of HIV and HHV-8 and the establishment of a large mother-infant cohort in Zambia to study those two viruses. We were the first to establish that HHV-8 can be transmitted perinatally and together with HIV contribute to the increase of Kaposi's sarcoma in children in Africa. More recently, in collaboration with CDC- GAP Zambia, we determined the early childhood infection rate of HHV-8. As such, we are ideally positioned to lead the proposed study, the first of its magnitude in the African setting. We have found perinatal transmission can occur in utero, but most HHV-8 infections occur during early childhood via horizontal transmission, with HHV-8 seroconversion occurring even in instances where the child's mother or entire household is HHV-8 negative. Moreover, HIV-1 is a major risk factor for HHV-8 infection, and we found HIV-1 infected children have a five-fold higher risk for infection by HHV-8 as compared to uninfected children, most likely due to immune suppression as a result of HIV-1 infection. It is possible that restoration of the immune response via ARV will reduce HHV-8 infection of HIV-1 positive children and enhance the immune response against HHV-8 in infected individuals. Unfortunately, the impact of ARV on HHV-8 transmission and on HHV-8 disease pathogenesis is unknown. We hypothesize that the treatment of HIV-1 infected children by ARV will substantially lower their risk of being infected by HHV-8 and reduce the risk of disease progression toward developing KS in infected children by enhancing their anti-HHV-8 immune response and reducing viral reactivation. The overall objective of the proposed study is to make use of our established study infrastructure to determine the impact of ARV treatment on HHV-8 transmission, on anti-HHV-8 immune response, and on viral reactivation. We propose to utilize relevant participants in our existing cohort and to recruit additional subjects for our proposed study, as appropriate. To test the validity of our hypothesis, we are proposing two aims. The first is to determine whether ARV treatment of HIV-1 infected children will reduce their susceptibility to HHV-8 infection. The second is to determine whether ARV treatment of HIV-1 and HHV-8 dually infected children will enhance their immune response against HHV-8 and reduce viral reactivation. We anticipate that the data generated through the proposed effort will be useful in the development of future intervention strategies to prevent HHV-8 transmission. PUBLIC HEALTH RELEVANCE: For the past 10 years we have studied the mother to child transmission of human herpesvirus-8 (HHV-8) or Kaposi's sarcoma-associated herpesvirus (KSHV), which is associated with Kaposi's sarcoma (KS), a devastating malignancy in AIDS patients in sub-Saharan Africa. With the recent introduction of anti-retroviral therapy (ARV) in Zambia, it is both timely and important to investigate the effects of ARV on HHV-8 infection. Our study will lead to a better understanding of the relative effects of ARV treatment on HHV-8 replication, and it may also lead to more effective KS treatment and prevention guidelines in HIV-infected children.

描述（由申请人提供）：Kaposi的肉瘤（KS）的发病率 - 与艾滋病毒/艾滋病密切相关的毁灭性恶性肿瘤在撒哈拉以南非洲国家（例如赞比亚）等抗逆转录病毒疗法（ARV）仍然很广泛。人类疱疹病毒8（HHV-8）或Kaposi的肉瘤相关疱疹病毒（KSHV）是与KS相关的病因学剂。我们的实验室因研究HIV和HHV-8的传播以及在赞比亚建立大型母亲队列以研究这两种病毒而被广泛认可。我们是第一个确定HHV-8可以通过围产期传播的人，并与艾滋病毒一起促进了非洲儿童Kaposi肉瘤的增加。最近，与赞比亚CDC-GAP合作，我们确定了HHV-8的幼儿感染率。因此，理想情况下，我们可以领导拟议的研究，这是其在非洲环境中的第一级。我们发现围产期传播可能发生在子宫内，但是大多数HHV-8感染在儿童早期通过水平传播发生，即使在孩子的母亲或整个家庭为HHV-8阴性的情况下，HHV-8血清转化也会发生。此外，HIV-1是HHV-8感染的主要危险因素，我们发现，与未感染的儿童相比，HHV-8感染HHV-8感染的风险更高五倍，这很可能是由于HIV-1感染了免疫抑制。通过ARV恢复免疫反应可能会降低HIV-8阳性儿童的HHV-8感染，并增强受感染个体中HHV-8的免疫反应。不幸的是，ARV对HHV-8传播和HHV-8疾病发病机理的影响尚不清楚。我们假设通过ARV对HIV-1感染的儿童的治疗将大大降低其被HHV-8感染的风险，并通过增强其抗HHV-8免疫反应并减少病毒重新激活，从而降低受感染儿童发展KS的风险。拟议研究的总体目的是利用我们既定的研究基础设施来确定ARV处理对HHV-8传播，抗HHV-8免疫反应以及病毒重新激活的影响。我们建议利用现有队列中的相关参与者，并在适当的研究中招募其他主题。为了检验我们的假设的有效性，我们提出了两个目标。首先是确定对HIV-1感染儿童的ARV治疗是否会降低其对HHV-8感染的敏感性。第二个是确定对HIV-1和HHV-8双感染儿童的ARV治疗是否会增强对HHV-8的免疫反应并减少病毒重新激活。我们预计，通过拟议的工作产生的数据将有助于制定未来的干预策略，以防止HHV-8传输。 公共卫生相关性：在过去的十年中，我们研究了母亲的人类疱疹病毒8（HHV-8）或Kaposi的肉瘤相关疱疹病毒（KSHV），这与Kaposi的Sarcoma（KS）有关，这与Kaposi的Sarcoma（ks）有关，这是艾滋病中的艾滋病患者的破坏性恶性。随着赞比亚最近引入抗逆转录病毒疗法（ARV），研究ARV对HHV-8感染的影响既及时又重要。我们的研究将更好地理解ARV治疗对HHV-8复制的相对影响，并且还可能导致更有效的KS治疗和预防HIV感染的指南。