MOLECULAR INTERACTIONS BETWEEN HIV-1 AND HHV-8

卡波西氏肉瘤(KS)是艾滋病患者中最常见的肿瘤，影响大约20%的艾滋病毒感染者。虽然艾滋病毒-1对KS的发展既不是必要的，也不是充分的，但艾滋病-KS被认为比其他形式的这种疾病更具侵袭性、传播性和抗药性。最近的研究发现，一种新的人类疱疹病毒，HHV-8，在几乎100%的KS皮损中。虽然HHV-8似乎对KS的发展至关重要，但目前尚不清楚哪些额外的辅助因素导致了AIDS-KS的侵袭性。人们通常认为，在艾滋病中诱导免疫抑制可以通过抑制抗病毒和免疫监测机制来复制HHV-8和发展KS。然而，与其他免疫抑制患者相比，仅有免疫抑制并不能解释KS在艾滋病患者中的压倒性流行，不能解释在感染HIV-1而不是HIV-2的患者中几乎唯一发生KS的原因，也不能解释在免疫抑制发生之前的艾滋病早期KS的频繁发生。在这个提议中，我们假设HIV-1和HHV-8之间发生了分子相互作用。从HIV-1感染细胞释放的HIV-1相关蛋白和/或细胞因子从潜伏期重新激活HHV-8，导致病毒载量增加，从而导致AIDS-KS的高频率和侵袭性。拟议的研究不仅将描述这两种病毒之间的相互作用，而且还将确定参与诱导病毒复制的病毒和/或细胞因素。然后，我们将扩展这一体外数据，并在完全由人类成分组成的体内模型中检查HIV-1和HHV-8之间的病毒相互作用。通过在未来三年内完成这三个目标，我们将对控制HHV-8和HIV-1病毒在体外和体内复制的分子机制有新的见解，确定HHV-8导致KS的关键辅助因素，如HIV-1，也将促进实验动物模型的发展，以进一步研究这种疾病。这样的模型将对设计艾滋病-KS的新疗法特别有用。

Kaposi's Sarcoma (KS) is the most common neoplasm in AIDS patients affecting approximately 20 percent of HIV infected individuals. While HIV-1 is neither necessary nor sufficient for the development of KS, AIDS-KS is recognized as more aggressive, disseminated and resistant to treatment that other forms of this disease. Recent studies have identified a new human herpesvirus, HHV-8, in virtually 100 percent of KS lesions. While it appears that HHV-8 is essential to the development of KS, it is currently unclear what additional co-factors are responsible for the aggressive nature of AIDS-KS. It is often assumed that induction of immunosuppression in AIDS allows for the replication of HHV-8 and development of KS by suppression of anti-viral and immunosurveillance mechanisms. However, immunosuppression alone can not explain the overwhelming prevalence of KS in AIDS patients in comparison with other immunosuppressed patient populations, the almost exclusive development of KS in patients infected with HIV-1, but not HIV-2, or the frequent occurrence of KS early in AIDS prior to the development of immunosuppression. In this proposal, we hypothesize that a molecular interaction occurs between HIV-1 and HHV-8. HIV-1 related proteins and/or cytokines released from HIV-1 infected cells reactivate HHV-8 from latency resulting in an increased viral load and, therefore, contributing to the high frequency and aggressive nature of AIDS- KS. The proposed studies will not only characterize the interaction between these two viruses but also identify the viral and/or cellular factors involved in induction of viral replication. We will then extend this in vitro data and examine viral interactions between HIV-1 and HHV-8 in an in vivo model composed entirely of human constituents. By completing these three aims over the next three years, we will gain new insight into the molecular mechanisms governing regulation of HHV-8 and HIV-1 viral replication both in vitro and in vivo Determining essential co-factors that are critical for HHV-8 to cause KS, such as HIV-1, will also facilitate development of experimental animal models to further investigate this disease. Such models will be particularly useful for devising new therapies for AIDS- KS.