Kaposi's sarcoma and human herpesvirus in Africa

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（如赞比亚）仍然非常普遍，其中抗逆转录病毒治疗（ARV）最近才变得可用。人类疱疹病毒-8（HHV-8）或卡波西肉瘤相关疱疹病毒（KSHV）是KS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一个大型母婴队列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。最近，我们与赞比亚CDC- GAP合作，确定了HHV-8的幼儿感染率。因此，我们处于领导拟议研究的理想地位，这是非洲环境中的第一次重大研究。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，即使在儿童的母亲或整个家庭都是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ARV治疗HIV-1感染儿童将大大降低他们被HHV-8感染的风险，并通过增强他们的抗HHV-8免疫应答和减少病毒再激活来降低感染儿童发生KS的疾病进展风险。拟议研究的总体目标是利用我们已建立的研究基础设施来确定ARV治疗对HHV-8传播、抗HHV-8免疫应答和病毒再活化的影响。我们建议利用现有队列中的相关受试者，并在适当情况下为我们的拟议研究招募更多受试者。为了验证我们假设的有效性，我们提出了两个目标。首先是确定对HIV-1感染儿童进行ARV治疗是否会降低他们对HHV-8感染的易感性。第二是确定对HIV-1和HHV-8双重感染儿童的ARV治疗是否会增强他们对HHV-8的免疫应答并减少病毒再激活。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.