Modulating the Impact of Critical Events in Early HIV Infection: Effect of Early ART Initiation and Alcohol Use

 描述(由申请人提供)：我们的总体目标是确定开始抗逆转录病毒治疗的时间和饮酒对艾滋病毒病程的影响，包括详细分析艾滋病毒感染后不久发生的重要事件。在HIV感染后立即开始抗逆转录病毒治疗(在FieBig阶段I-II期间)在很大程度上会导致较小的HIV储备库和较低的HIV相关全身炎症，这与非艾滋病的发病率和死亡率有关。立即抗逆转录病毒治疗还可以减少艾滋病毒相关的细菌易位，并可能防止生物失调，这是一种与全身炎症增加有关的肠道微生物区系的改变。然而，立即干预通常是不可行的，需要更多关于在以后的时间点开始抗逆转录病毒治疗的后果的信息，但仍然是在获得之后的早期。这项拟议的研究将在秘鲁利马进行，我们对180名患有急性(抗体-，艾滋病毒RNA+)或最近(=3个月)艾滋病毒感染的MSM进行了队列研究。在我们的队列中，约50%的感染艾滋病毒的男男性同性恋者存在酒精使用障碍，这一比例是秘鲁普通人群中男性的四倍。尽管酒精在HIV发病机制和病程中的作用尚不清楚，但一些研究表明与加速疾病进展有关。在动物模型和临床研究中，急性和慢性饮酒都与细菌易位和天然免疫系统的激活有关，这可能导致促炎细胞因子的增加。酒精的作用类似于感染后早期HIV诱导的细菌易位和促炎细胞因子的变化，以及它们在ART启动前后对HIV病程的影响尚不清楚。具体目标1：确定即刻、早期和延迟的抗逆转录病毒治疗方案的相对长期益处。我们将研究MSM被诊断为急性或最近感染HIV的1.5年和3.5年后的结果。我们将根据ART开始的时间来检查3组的结果：a)即刻：在FI-II期间(N~30)，b)早期：在FII-V期间(N~50)或c)延迟：在诊断后24周(N~80)。我们预计，随着时间的推移，FiII-V组和延迟治疗组的CD4+T细胞计数和外周炎症标志物将接近立即治疗组(FI-II)的水平；相反，我们预计那些在“早期”或“延迟”时间点开始抗逆转录病毒治疗的患者，胃肠道微生物组和HIV储存库将发生持续的变化。具体目标2：确定酒精使用对即刻开始抗逆转录病毒治疗与早期抗逆转录病毒治疗与延迟抗逆转录病毒治疗的相对长期益处的影响。我们将研究酒精使用对艾滋病毒感染关键事件的影响。我们假设，剂量依赖的酒精诱导的变化将加剧艾滋病毒的负面影响，并导致更高水平的生物失调和炎症，更高的早期血浆艾滋病毒RNA，以及更大的“种子”和持续的艾滋病毒DNA在高水平饮酒的参与者。我们将评估病毒载量、胃肠道微生物组和元基因组学、促炎细胞因子、msRNA的产生，并分析在ART开始之前所有受试者和接受ART持续病毒抑制的受试者中酒精使用的影响。

 DESCRIPTION (provided by applicant): Our overall objective is to determine the influence of timing of ART initiation and alcohol consumption on HIV disease course, including detailed analysis of important events occurring shortly after HIV acquisition. ART initiation immediately after HIV infection (during Fiebig stages I-II) largely results in smaller HIV reservoir and lower HIV-associated systemic inflammation, which has been linked to non-AIDS morbidity and mortality. Immediate ART also reduces HIV-associated bacterial translocation and may prevent dysbiosis, an alteration of the intestinal microbiota that has been linked to increased systemic inflammation. Immediate intervention is not, however, generally feasible and more information is required about the consequences of starting ART at later time-points, but still early after acquisition. The proposed study will be conducted in Lima, Peru, in our cohort of 180 MSM with acute (Ab-, HIV RNA+) or recent (= 3 months) HIV infection. Alcohol use disorder is present in ~50% of HIV-infected MSM in our cohort, which is four times higher than that seen among males in the general Peruvian population. Although the role of alcohol use in HIV pathogenesis and disease course remains unclear, some studies show a correlation with accelerated disease progression. In animal models and clinical studies, both acute and chronic alcohol consumption have been linked to bacterial translocation and activation of the innate immune system, which can lead to increases in pro-inflammatory cytokines. The effects of alcohol resemble early post-infection changes in bacterial translocation and pro-inflammatory cytokines induced by HIV and their impact on HIV disease course before and after ART initiation remain unexplored. Specific Aim 1: To determine the relative long-term benefits of immediate vs. early vs. delayed ART initiation. We will study outcomes after 1.5 and 3.5 years in MSM diagnosed with acute or recent HIV infection. We will examine outcomes in 3 groups based on time of ART initiation: a) immediate: during FI-II (N~30), b) early: during FIII-V (N~50) or c) delayed: at 24 weeks after diagnosis (N~80). We anticipate that CD4+ T cell counts and peripheral inflammatory markers in the FIII-V group and the delayed group will approach those in the immediate treatment group (FI-II) over time; in contrast, we expect that those started ART at "early" or "delayed" time point will have persistent changes in the GI microbiome and in the HIV reservoir. Specific Aim 2: To determine the impact of alcohol use on the relative long-term benefits of immediate vs. early vs. delayed initiation of ART. We will examine the impact of alcohol use on critical events in HIV infection. We hypothesize that dose-dependent alcohol-induced changes will compound the negative effects of HIV and lead to greater levels of dysbiosis and inflammation, higher early plasma HIV RNA, and greater "seeding" and persistence of HIV DNA in participants with high-level alcohol use. We will assess viral load, GI microbiome and metagenomics, pro-inflammatory cytokines, production of msRNA and analyze the impact on alcohol use in all subjects prior to ART initiation and among ART-adherent participants with persistent viral suppression.