Alcohol Affects Viral Dynamics to Accelerate HIV Disease Progression

酒精影响病毒动力学，加速艾滋病毒疾病进展

• 批准号: 9121783
• 负责人: Spencer Robichaux
• 金额: $ 3.75万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-04 至 2018-08-03
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9121783
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Address; Adherence; Affect; Alcohol abuse; Alcohols; Animals; Antiviral Therapy; Behavioral; Biological; Cells; Chronic; Chronic Disease; Clinical Management; Comorbidity; Complex; Control Animal; DNA; Data; Depressed mood; Development Plans; Disease; Disease Progression; Doctor of Philosophy; Drug resistance; Ensure; Environment; Epidemiology; Evolution; Face; Fellowship; Fostering; Funding; Future; Generations; Genetic Transcription; Genotype; Goals; HIV; HIV Infections; High Prevalence; Immunity; Immunology; Individual; Infection; Inflammatory; Kinetics; Life; Link; Literature; Longevity; Longitudinal Studies; Lymph Node Tissue; Macaca; Macaca mulatta; Mediator of activation protein; Mentorship; Microbiology; Modeling; Mononuclear; National Institute on Alcohol Abuse and Alcoholism; Nature; Outcome; Parasitology; Pathogenicity; Patients; Peripheral; Population; Predisposition; Publishing; Qualifying; Regimen; Research; Research Design; Research Personnel; Risk; SIV; Sampling; Scientist; Technology; Testing; Therapeutic Intervention; Tissues; Training; Training Programs; Translational Research; Treatment Protocols; Variant; Viral; Viral Load result; Viral reservoir; Viremia; Virus; Virus Diseases; Virus Replication; Vulnerable Populations; alcohol consequences; alcohol effect; alcohol research; alcohol use disorder; antiretroviral therapy; base; binge drinking; career; chronic alcohol ingestion; cohort; design; disease transmission; innovation; insight; lymph nodes; member; next generation sequencing; prevent; public health relevance; rectal; skills; success; therapy development; training opportunity; translational study; transmission process; treatment strategy; viral DNA; viral RNA; virus host interaction

 DESCRIPTION (provided by applicant): The life-span of people living with HIV has dramatically increased due to effective antiretroviral therapy, and we are now faced with managing HIV as a chronic disease. Alcohol use disorder (AUD) is a significant HIV comorbidity that has been shown to negatively affect HIV disease and is associated with increased risk of HIV transmission, increased viremia, and a more accelerated progression to AIDS. Understanding the biological basis by which alcohol exacerbates HIV disease progression remains a major goal in the search for new innovative treatment strategies and the clinical management of HIV in chronically-infected populations. It is widely appreciated that the primary mediator of HIV disease is the virus, and several recent studies have begun to focus on early viral kinetics to better understand the nature of disease course. These studies have shown that rapid viral dissemination in reservoir tissues shortly after infection sets the future course for disease progression. For this reason, understanding how chronic alcohol consumption affects viral dynamics over the course of disease will provide new, multifaceted insights to the complex effects of alcohol on HIV disease. Recent studies using the SIV-infected macaque model have shown chronic binge alcohol (CBA) consumption affects early viral:host interactions leading to an increased susceptibility to intrarectal SIV challenge. Additionally, our preliminary data demonstrates CBA consumption alters viral dynamics by promoting genotypic selection and increasing viral reservoir expression. Taken together, the literature and our preliminary finding, support our central hypothesis that chronic alcohol consumption affects the establishment of founder viral reservoirs and their subsequent replication dynamics to accelerate disease progression. As part of the training of the applicant, the proposed studies will use an innovative approach to test the predictions that: 1) CBA administration increases the number and genotypic diversity of founder viral genotypes transmitted to macaques inoculated with SIVmac251, 2) CBA administration fosters the selection of SIV genotypes with increased expression kinetics in tissue reservoirs of macaques at set point, and 3) CBA administration increases compartment-specific viral expression, promoting SIV genotypic selection, despite continuous antiretroviral therapy (ART). These studies will identify how alcohol influences early viral selection and replication in the host and allow us to longitudinally assess their impact on disease progression. Furthermore, this study will aid the clinical management of HIV patients with AUD by providing evidence to optimize the selection and initiation of ART regimens and pre-exposure therapies.

 描述（由适用提供）：由于有效的抗逆转录病毒疗法，艾滋病毒感染者的寿命大大增加了，现在我们面临将艾滋病毒作为一种慢性疾病的管理。酒精使用障碍（AUD）是一种重要的HIV合并症，已证明对HIV疾病产生负面影响，并且与HIV传播的风险增加，病毒血症增加以及对艾滋病的进展更加加速有关。了解饮酒加剧HIV疾病进展的生物学基础仍然是寻找新的创新治疗策略和在慢性感染人群中HIV的临床管理的主要目标。人们普遍认为，艾滋病毒疾病的主要介体是病毒，最近的一些研究开始着重于早期病毒动力学，以更好地了解疾病病程的性质。这些研究表明，感染后不久，储层时机中的快速病毒传播设定了未来的疾病进展过程。因此，了解长期饮酒如何影响疾病过程中的病毒动态，将为酒精对艾滋病毒疾病的复杂作用提供新的多方面见解。使用SIV感染的猕猴模型的最新研究表明，慢性暴饮暴食（CBA）消耗会影响早期病毒：宿主相互作用，导致对直肠内SIV攻击的敏感性增加。此外，我们的初步数据表明，CBA消耗通过促进基因型选择和增加病毒储存库表达来改变病毒动力学。综上所述，文献和我们的初步发现支持我们的中心假设，即慢性饮酒会影响创建者的病毒储层及其随后的复制动力，以加速疾病的进展。作为申请人培训的一部分，拟议的研究将使用一种创新的方法来测试以下预测：1）CBA给药会增加传播到SIVMAC251，2）CBA给药的猕猴的创建者病毒基因型的数量和基因型多样性，并促进了Siv Genotepes的选择，并在Siv Genotepes中促进了STERPATE的选择。增加了区室特异性病毒表达，促进了SIV基因型选择，多皮持续抗逆转录病毒疗法（ART）。这些研究将确定酒精如何影响宿主的早期病毒选择和复制，并允许我们纵向评估其对疾病进展的影响。此外，这项研究将通过提供证据来优化艺术方案和暴露前疗法的选择和主动性，从而有助于AUD的HIV患者的临床管理。