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

HIV 和 HHV-8 混合感染对非洲抗逆转录病毒治疗效果的影响

• 批准号: 8278460
• 负责人: Corey Casper
• 金额: $ 29.78万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-20 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8278460
• 关键词: Acquired Immunodeficiency Syndrome; Africa; Africa South of the Sahara; Antibodies; Applications Grants; Basic Science; Biology; Blood specimen; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell Culture Techniques; Cells; Characteristics; Chronic; Clinical; Clinical Research; Clinical Trials; Cohort Studies; Country; Cytomegalovirus; Cytotoxic T-Lymphocytes; DNA biosynthesis; Data; Detection; Development; Disease; Disease Progression; Enrollment; Epidemic; Epidemiology; Flare; Frequencies; Functional disorder; Ganciclovir; Genes; Genital system; HIV; Health; High Prevalence; Highly Active Antiretroviral Therapy; Human Herpesvirus 8; Immune; Immunologic Factors; In Vitro; Incidence; Individual; Infection; Inflammatory; Kaposi Sarcoma; Kinetics; Knowledge; Lead; Long Terminal Repeats; Lymphocyte Count; Lymphoproliferative Disorders; Lytic; Malignant Neoplasms; Measurement; Measures; Modeling; Mucous Membrane; Multicentric Angiofollicular Lymphoid Hyperplasia; Natural History; Nucleosides; Observational Study; Opportunistic Infections; Participant; Pathway interactions; Patients; Pattern; Persons; Phenotype; Phosphatidylinositols; Phosphotransferases; Plasma; Population; Prevalence; Prevention strategy; Protease Inhibitor; Proteins; Regimen; Research; Rest; Reverse Transcriptase Inhibitors; Role; Sampling; Series; Severities; Site; Speed; Staging; Surface; Syndrome; System; Testing; Thymidine Kinase; Time; Treatment Efficacy; Uganda; Viral Load result; Virus; Virus Diseases; Virus Replication; Work; antiretroviral therapy; base; clinical care; cohort; design; disease transmission; improved; latency-associated nuclear antigen; lytic replication; mucosal site; neutralizing antibody; pathogen; peripheral blood; prevent; progenitor; prospective; public health relevance; reconstitution; response; translational study; transmission process

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.

描述（由申请人提供）：卡波西肉瘤（KS）是全球最常见的与hiv相关的恶性肿瘤，可归因于人类疱疹病毒8 （HHV-8）感染。在美国和非洲艾滋病毒感染率高的人群中，HHV-8合并感染极为常见。HIV和HHV-8合并感染对HIV和HHV-8相关疾病的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。在美国，高效抗逆转录病毒疗法（HAART）降低了KS的发病率和严重程度，但在非洲可能没有那么有效，因为非洲的HHV-8疾病负担要高得多，免疫重建炎症综合征（IRIS）通常会导致HHV-8相关疾病的恶化。基于先前和正在进行的研究，我们的团队开发了一个概念模型，该模型假设：a)在HIV和HHV-8共同感染的个体中，每种病毒协同作用以增强彼此的复制；B)使用HAART减少HHV-8复制的方式既依赖于也独立于其对HIV复制的影响；C) HHV-8感染者分为在外周血和粘膜部位频繁复制的人和没有复制的人；我们提出了一项对350名HIV/HHV-8合并感染的乌干达人进行HAART的前瞻性队列研究，以评估以下具体目的：(1)确定在HAART开始时以及之后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)确定在开始HAART治疗时以及之后2年的HHV-8感染的病毒学特征是否影响粘膜和外周血部位HIV的抑制；(3)描述hhv -8相关IRIS的频率和相关因素。