Kaposi's sarcoma and human herpesvirus in Africa

描述(申请人提供)：卡波西氏肉瘤(KS)--一种与艾滋病毒/艾滋病密切相关的破坏性恶性肿瘤--的发病率在赞比亚等撒哈拉以南非洲国家仍然非常广泛，在这些国家，抗逆转录病毒疗法(ARV)最近才出现。人类疱疹病毒8型(HHV-8)或卡波西氏肉瘤相关疱疹病毒(KSHV)是与KS相关的病原体。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。我们第一个确定HHV-8可以通过围产期传播，与艾滋病毒一起导致非洲儿童卡波西肉瘤的增加。最近，我们与CDC-GAP赞比亚合作，确定了HHV-8儿童早期感染率。因此，我们处于领导拟议研究的理想位置，这是其在非洲背景下的第一个重大研究。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，即使在孩子的母亲或整个家庭HHV-8阴性的情况下也会发生HHV-8血清转换。此外，HIV-1是HHV-8感染的主要风险因素，我们发现HIV-1感染儿童感染HHV-8的风险是未感染儿童的五倍，最有可能是由于HIV-1感染导致免疫抑制。通过ARV恢复免疫应答，有可能减少HIV-1阳性儿童的HHV-8感染，增强感染者对HHV-8的免疫应答。遗憾的是，ARV对HHV-8传播和HHV-8疾病发病机制的影响尚不清楚。我们推测，用抗逆转录病毒治疗HIV-1感染的儿童将大大降低他们感染HHV-8的风险，并通过增强他们的抗HHV-8免疫反应和减少病毒的重新激活，减少感染儿童发展为KS的疾病进展风险。拟议研究的总体目标是利用我们建立的研究基础设施来确定ARV治疗对HHV-8传播、抗HHV-8免疫反应和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，并酌情为拟议研究招募更多受试者。为了检验我们假设的正确性，我们提出了两个目标。第一个是确定对感染HIV-1的儿童进行ARV治疗是否会降低他们对HHV-8感染的易感性。第二个是确定对HIV-1和HHV-8双重感染的儿童进行ARV治疗是否会增强他们对HHV-8的免疫反应，并减少病毒的重新激活。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战略，以防止HHV-8传播。

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.