Impact of HIV and HHV-8 Co-Infection on Antiretroviral Therapy Efficacy in Africa

描述(申请人提供)：卡波西肉瘤(KS)是世界上最常见的与艾滋病毒相关的恶性肿瘤，可归因于感染人类疱疹病毒8型(HHV-8)。在美国和非洲艾滋病毒感染率较高的人群中，HHV-8混合感染非常常见。艾滋病毒和HHV-8混合感染对艾滋病毒和HHV-8相关疾病的自然历史的影响尚不清楚。然而，很明显，艾滋病毒会增加KS的发病率和严重程度，我们的初步数据发现，HHV-8感染也可能加剧艾滋病毒疾病的进展。高效抗逆转录病毒疗法(HAART)降低了KS在美国的发病率和严重程度，但在非洲可能没有那么有效，因为那里HHV-8疾病的负担要高得多，免疫重建炎症综合征(IRIS)通常会导致HHV-8相关疾病的恶化。根据以前和正在进行的研究，我们小组开发了一个概念模型，该模型假设：A)在HIV和HHV-8混合感染的个体中，两种病毒协同作用增强对方的复制；B)使用HAART以一种依赖和独立于其对HIV复制的影响的方式减少HHV-8的复制；C)HHV-8感染者分为在外周血液和粘膜部位频繁复制的人和没有复制的人；和D)持续的HHV-8复制可能会限制HAART抑制HIV复制的效果。我们建议对350名开始HAART的HIV/HHV-8混合感染的乌干达人进行前瞻性队列研究，以评估以下具体目标：(1)确定HAART开始时和随后2年内HIV感染的临床和病毒学表现是否影响对HHV-8粘膜和外周血复制的抑制；(2)确定HAART开始时HHV-8感染的病毒学特征是否影响粘膜和外周血部位对HIV的抑制；(3)研究HHV-8相关IRIS的发生频率及其相关因素。 公共卫生相关性：这项建议试图了解艾滋病毒和人类疱疹病毒8型混合感染可能如何影响艾滋病毒和HHV-8相关疾病的自然历史。从这项建议中获得的知识可能会导致改进在全球大多数艾滋病毒感染者中使用高效抗逆转录病毒疗法的战略，这些人是艾滋病毒和HHV-8共同感染的人，更好的预防措施和艾滋病毒相关癌症的治疗，以及提高HAART在防止艾滋病毒疾病进展和传播方面的有效性的新战略。

DESCRIPTION (provided by applicant): Kaposi sarcoma (KS), the most common HIV-associated malignancy worldwide, is attributable to infection with human herpesvirus 8 (HHV-8). In populations in the US and Africa with high prevalence of HIV infection, HHV-8 co-infection is extremely common. The ramifications of HIV and HHV-8 co-infection for the natural history of HIV and HHV-8 associated diseases are unknown. However, it is clear that HIV increases the incidence and severity of KS, and our preliminary data find that HHV-8 infection may also exacerbate the progression of HIV disease. Highly active antiretroviral therapy (HAART) reduces the incidence and severity of KS in the US, but may not be as effective in Africa where the burden of HHV-8 disease is substantially higher and immune reconstitution inflammatory syndrome (IRIS) commonly leads to a worsening of HHV-8-associated disease. Based on previous and ongoing research, our group has developed a conceptual model which posits that: A) among individuals co-infected with HIV and HHV-8, each virus acts synergistically to enhance the other's replication; B) the use of HAART reduces HHV-8 replication in a manner which is both dependent and independent of its effect on HIV replication; C) persons with HHV-8 infection are divided between those with frequent replication in the peripheral blood and at mucosal sites and those without; and D) persistent HHV-8 replication may limit the efficacy of HAART in suppressing HIV replication We propose a prospective cohort study of 350 HIV/HHV-8 co-infected Ugandans initiating HAART to evaluate the following Specific Aims: (1) Determine whether the clinical and virologic manifestations of HIV infection at the time of HAART initiation, and in the 2 years following, impact the suppression of HHV-8 mucosal and peripheral blood replication; (2) Determine whether the virologic characteristics of HHV-8 infection at the time of HAART initiation, and in the 2 years following, impact the suppression of HIV at mucosal and peripheral blood sites; (3) Characterize the frequency and correlates of HHV-8-associated IRIS. PUBLIC HEALTH RELEVANCE: This proposal seeks to understand how HIV and human herpesvirus 8 co-infection may impact the natural history of both HIV and HHV-8 associated disease. Knowledge gained from this proposal may lead to improved strategies for the use of highly active antiretroviral therapy among the majority of HIV-infected individuals worldwide who are HIV and HHV-8 co-infected, better preventative measures and treatments for HIV- associated cancers, and new strategies for increasing the efficacy of HAART in preventing HIV disease progression and transmission.