Reservoir activity and recrudescent virus composition in HIV and SIV rebound

随着艾滋病毒/艾滋病研究领域开始努力治愈艾滋病毒-1感染，对水库的洞察 面对抑制性抗逆转录病毒疗法(ART)，维持病毒的持久性是必不可少的。最受关注的 一直在研究使用循环中的CD4+T细胞进行前病毒和病毒副产物分析(VOA)的特征 这可能会限制对组织中储存库的性质以及更重要的来源的了解能力 在ART中断后复发的病毒。此外，这些方法不会揭示 非CD4+T细胞，如组织巨噬细胞，对病毒持续和反弹的潜在贡献。 病毒血症反弹的时间和构成可能反映了病毒血症来源的性质 来源和宿主的抗病毒免疫质量对其征收。项目3将评估病毒库 治疗中断前的活动，以及反弹的病毒血症的成分，以获得 深入了解宿主抗病毒免疫影响病毒反弹活性的病毒学机制。 项目1将提供已完成和计划的人类治疗性疫苗试验(BCN)的纵向样本 ATI、RISVAC03、BCN02和AELIX003)。SIV猕猴模型(项目2)将纵向提供 治疗后采集ART抑制、RhCMVd10/SIV疫苗接种猕猴的血液和组织 中断。至关重要的是，这两个项目都允许对反弹的病毒血症进行最早的采样，这最有可能 反映了它的起源于在艺术压制下持续存在的水库。 我们推测，由RhCMVd10/SIV疫苗接种猕猴和在人类身上引发的免疫反应 通过病毒载量“数据知情的”疫苗，影响病毒宿主的活动，这体现在对 病毒反弹的时间以及病毒库的活性和组成。为了进一步研究这一假设，我们 提出以下具体目标： 目的是(I)评估治疗性疫苗接种对病毒库活动的影响，(Ii)评估 治疗性疫苗接种对反弹病毒成分的影响，以及(Iii)确定巨噬细胞是否- 回升病毒血症中的热带病毒起源于巨噬细胞。

As the HIV/AIDS research field embarks on an endeavor to cure HIV-1 infection, insight into the reservoirs that sustain viral persistence in the face of suppressive antiretroviral therapy (ART) is essential. Most of the focus has been on characterization of proviruses and viral outgrowth assays (VOA) using circulating CD4+ T-cells that may have limited ability to inform on the nature of the reservoirs in tissues and more importantly, the origin of the viruses that recrudesce upon ART interruption. Furthermore, these approaches do not reveal the potential contribution of non-CD4+ T-cells, such as tissue macrophages, to viral persistence and rebound. The timing and composition of rebounding viremia is likely to reflect the nature of the reservoir from which it originated and the quality of host antiviral immunity levied against it. Project 3 will assess viral reservoir activity prior to treatment interruption, as well as the composition of rebounding viremia, to gain insight into the virologic mechanisms whereby host antiviral immunity impacts viral rebound activity. Project 1 will provide longitudinal samples from completed and planned human therapeutic vaccine trials (BCN ATI, RISVAC03, BCN02 and AELIX003). The SIV macaque model (Project 2) will provide longitudinally sampled blood and tissues from ART-suppressed, RhCMVd10/SIV-vaccinated macaques after treatment interruption. Crucially, both projects allow the earliest sampling of rebounding viremia, which is most likely to reflect its origins in the reservoirs that persist under ART suppression. We hypothesize that immune responses in macaques elicited by RhCMVd10/SIV vaccination and in humans by a viral load “data-informed” vaccine, impact viral reservoir activity and that this is manifest by an impact on time to viral rebound as well as activity and composition of the viral reservoir. To pursue this hypothesis, we propose the following specific aims: The objectives are to (i) evaluate the effect of therapeutic vaccination on viral reservoir activity, (ii) assess the effect of therapeutic vaccination on rebounding virus composition, and (iii) determine whether macrophage- tropic viruses present in rebounding viremia have a macrophage origin.