Project 3: Viral dynamics of Remission or Rebound Following Early Treatment of SIV

摘要 从受感染个体抑制人类免疫缺陷病毒（HIV-1）是 抗逆转录病毒疗法（ART）。随着抗逆转录病毒疗法的出现，在这方面取得了重大进展 养生法然而，尽管在感染者中持续抑制血浆病毒血症低于可检测限度， 患者多年的ART方案，复制能力的病毒仍然可以从各种恢复， 在宿主内的位点，最明显的是来自长寿命的静态记忆CD 4 + T淋巴细胞。这种病毒 艾滋病毒感染是根除和清除艾滋病毒感染或持续 目前，我们对ART接受者中HIV储库的理解是 不完整评估急性感染期间早期ART启动对储库大小影响的数据如下： 有限的，特别是在组织中，作为缓解或控制HIV-1的病毒学和免疫学替代物。 我的实验室最近的数据表明，SIV在很早的时候就建立了持久的病毒库 感染[1]。然而，非常早期的ART可能会限制HIV细胞储存库的播种和扩张[2-4]。 此外，在最早阶段开始的抗逆转录病毒治疗可能会显著限制病毒的大小、位置和遗传多样性。 HIV-1储库，从而提高病毒学缓解的机会。有效的潜伏期 逆转剂（LRA）或其他免疫疗法递送到这些早期ART治疗的储库， 不清楚 因此，需要详细的机制研究来确定早期ART对病毒学和免疫学的影响。 免疫结果与实现艾滋病毒缓解和持久的病毒控制有关， 停止ART [5]。这类调查在本提案中有详细说明。 为了研究这些假设，我们提出以下具体目标： 1.确定早期ART对早期SIV储层性质和分布的影响 病毒建立 2.评估SIV分布和克隆扩张在ART开始和ART停止后。 3.确定联合免疫治疗（TLR 7激动剂和PD-L1）对稳定性的影响 停止抗逆转录病毒疗法后的病毒库。

ABSTRACT The suppression of Human Immunodeficiency Virus (HIV-1) from infected individuals is the ultimate goal of antiretroviral therapy (ART). Major advances have been made towards this end with the advent of ART regimens. However, despite the sustained suppression of plasma viremia below detectable limits in infected patients for many years on ART regimens, replication competent virus can still be recovered from a variety of sites within the host, and most notably from long-lived quiescent memory CD4+ T lymphocytes. This viral reservoir represents the final impediment to the eradication and clearance of HIV infection or to a sustained virologic remission in the absence of ART. Currently, our understanding of HIV reservoirs in ART recipients is incomplete. Data assessing the impact of early ART initiation during acute infection on reservoir size are limited, especially in the tissues, as are virologic and immunologic surrogates of remission or control of HIV-1. Recent data from my laboratory has shown that persistent viral reservoirs are established very early in SIV infection [1]. However, very early ART can limit the seeding and expansion of cellular reservoirs of HIV [2-4]. Moreover, ART initiated in the earliest stages could significantly limit the size, location and genetic diversity of the HIV-1 reservoir, thereby improving the chance of a virologic remission. The efficacy of potent latency reversal agents (LRAs) or other immunotherapy delivered to very these early ART-treated reservoirs is unclear. Thus, detailed mechanistic studies are needed to define the impact of early ART on virological and immunologic outcomes that are relevant to achieving HIV remission and durable virus control after the cessation of ART [5]. Such investigations are detailed in this proposal. To investigate these hypotheses, we propose the following Specific Aims: 1. Determine the impact of early ART on the nature and distribution of the SIV reservoir during early viral establishment. 2. Assess SIV distribution and clonal expansion during ART initiation and after ART cessation. 3. Determine the impact of combination immunotherapy (TLR7 agonist and PD-L1) on the stability of the viral reservoir after ART cessation.