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Kaposi's sarcoma and human herpesvirus in Africa

非洲的卡波西肉瘤和人类疱疹病毒

基本信息

批准号：
9061047
负责人：
Charles Wood
金额：
$ 60万
依托单位：
UNIVERSITY OF NEBRASKA LINCOLN
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-07-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9061047
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 Collaborations Country Data Development Diagnosis Disease Disease Progression Epidemic Frequencies Future Goals HIV HIV-1 Health Herpesviridae Horizontal Disease Transmission Household Human Human Herpesvirus 8 Immune Immune response Immunosuppression Incidence Individual Infant Infection Intervention Kaposi Sarcoma Laboratories Lead Literature Malignant Childhood Neoplasm 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 restoration seroconversion transmission process

项目摘要

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.

描述（由申请人提供）：卡波西肉瘤（KS）——一种与艾滋病毒/艾滋病密切相关的毁灭性恶性肿瘤——的发病率在撒哈拉以南非洲国家仍然非常普遍，例如赞比亚，那里的抗逆转录病毒疗法（ARV）最近才开始可用。人类疱疹病毒-8 （HHV-8）或卡波西肉瘤相关疱疹病毒（KSHV）是与KS相关的病原。我们的实验室因其对艾滋病毒和HHV-8传播的研究以及在赞比亚建立了一个大型母婴队列来研究这两种病毒而得到广泛认可。我们是第一个确定HHV-8可以在围产期传播，并与艾滋病毒一起导致非洲儿童卡波西肉瘤的增加的人。最近，我们与赞比亚疾控中心GAP合作，确定了HHV-8的幼儿感染率。因此，我们处于领导这项拟议研究的理想地位，这是非洲环境中第一次如此大规模的研究。我们发现围产期传播可以发生在子宫内，但大多数HHV-8感染发生在儿童早期，通过水平传播，即使在儿童的母亲或整个家庭都是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HIV-1感染儿童感染HHV-8的风险比未感染儿童高5倍，很可能是由于HIV-1感染导致的免疫抑制。通过ARV恢复免疫应答可能会减少HIV-1阳性儿童的HHV-8感染，并增强感染个体对HHV-8的免疫应答。不幸的是，ARV对HHV-8传播和HHV-8疾病发病机制的影响尚不清楚。我们假设，通过增强儿童的抗HHV-8免疫反应和减少病毒再激活，ARV治疗HIV-1感染儿童将大大降低他们感染HHV-8的风险，并降低感染儿童疾病向KS发展的风险。拟议研究的总体目标是利用我们已建立的研究基础来确定抗逆转录病毒治疗对HHV-8传播、抗HHV-8免疫反应和病毒再激活的影响。我们建议在我们现有的队列中使用相关的参与者，并在适当的情况下为我们的研究招募额外的受试者。为了检验我们假设的有效性，我们提出了两个目标。首先是确定抗逆转录病毒药物治疗HIV-1感染儿童是否会降低他们对HHV-8感染的易感性。二是确定HIV-1和HHV-8双重感染儿童的抗逆转录病毒治疗是否会增强他们对HHV-8的免疫反应并减少病毒再激活。我们预计，通过拟议的努力产生的数据将有助于制定未来的干预策略，以防止HHV-8的传播。