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

描述（由申请方提供）：卡波西肉瘤（KS）是全球最常见的HIV相关恶性肿瘤，可归因于人类疱疹病毒8型（HHV-8）感染。在美国和非洲艾滋病毒感染率高的人群中，HHV-8合并感染非常常见。HIV和HHV-8共感染对HIV和HHV-8相关疾病自然史的影响尚不清楚。然而，很明显，HIV增加了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HIV疾病的进展。高效抗逆转录病毒疗法（HAART）在美国降低了KS的发病率和严重程度，但在非洲可能不那么有效，因为非洲HHV-8疾病的负担显著更高，免疫重建炎症综合征（IRIS）通常导致HHV-8相关疾病的恶化。 基于以前和正在进行的研究，我们小组已经开发了一个概念模型，该模型假定：A）在同时感染HIV和HHV-8的个体中，每种病毒协同作用以增强另一种病毒的复制; B）HAART的使用以既依赖于又独立于其对HIV复制的影响的方式减少HHV-8复制; C）具有HHV-8感染的人被分为在外周血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复制可能限制HAART抑制HIV复制的功效。（1）确定在HAART开始时以及随后2年内HIV感染的临床和病毒学表现是否影响HHV-8粘膜和外周血复制的抑制;（2）确定HAART开始时和随后2年内HHV-8感染的病毒学特征是否影响粘膜和外周血部位的HIV抑制;（3）分析HHV-8相关IRIS的频率和相关因素。

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.