Central memory CD4 T cell infection: key role in ART response and HIV persistence

描述：治愈HIV感染的一个主要障碍是我们对哪些因素调节对抗逆转录病毒治疗（ART）的免疫反应以及潜伏HIV库的建立和持续存在的不完全理解。虽然已经确定HIV优先感染记忆性CD4 T细胞，但尚不清楚HIV感染在各种CD4 T细胞亚群中的相对分布是否以及在多大程度上影响：(i) CD4 T细胞重构的程度，（ii）残余免疫激活/炎症的程度，以及（iii）抗逆转录病毒治疗期间持续HIV库的大小。这些问题与HIV感染者（PLHIV）高度相关，因为靶向特定的CD4 T细胞亚群可能是治愈HIV感染的潜在优先事项。CD4中枢记忆T细胞（TCM）是一种长寿、自我更新的细胞，对CD4 T细胞稳态和整体免疫功能起着至关重要的作用。最近在非人灵长类动物HIV感染模型中产生的证据表明，CD4 TCM感染是决定感染结果的关键因素。在恒河猴的致病性SIV感染中，感染水平和CD4 TCM的消耗决定了艾滋病的进展速度，而接种疫苗的动物中CD4 TCM的保存与对SIV感染的抗性有关。此外，在白眉猴非致病性SIV感染中，CD4低水平的中医感染是抗艾滋病的关键机制。与保护中药免受感染的重要性以及中药比TEM具有更长的半衰期的发现相一致，我们发现在抗逆转录病毒治疗的PLHIV中，CD4中药是受感染CD4 T细胞的最大储存库。基于这些发现，我们提出了一种新的、范式转换的模型，根据该模型，在抗逆转录病毒治疗期间，受感染CD4 T细胞的模式比免疫激活、病毒复制和受感染细胞总数的总体水平更重要，这决定了CD4 T细胞重构的幅度和病毒库的大小。在这里，我们将验证以下假设：在血液和淋巴结中，CD4 TCM感染(i)对免疫恢复和残余免疫激活的程度至关重要[目的1]；（ii）是抗逆转录病毒治疗后HIV库的大小和稳定性的一个预后因素[目的2]。此外，我们正在提出一系列机制研究，旨在确定CD4 TCM感染的分子相关因素，并设计可以保护这些细胞免受感染的治疗干预[Aim 3]。我们认为拟议的研究与人类健康高度相关。通过测试一个彻底创新的假设，这些研究将为抗逆转录病毒疗法免疫反应质量的机制以及由此产生的HIV病毒库的大小/持久性提供前所未有的新见解。如果我们的假设得到证实，这些研究将表明，旨在保护CD4 TCM免受感染的新策略应该是旨在治疗HIV感染的干预措施的关键组成部分。

DESCRIPTION: A major obstacle to cure HIV infection is our incomplete understanding of what factors regulate the immunologic response to antiretroviral therapy (ART) and the establishment and persistence of the latent HIV reservoir. Although it is well established that HIV preferentiall infects memory CD4 T cells, it is still unclear whether and to what extent the relative distributio of HIV infection within the various CD4 T cell subsets influences: (i) the magnitude of CD4 T cell reconstitution, (ii) the extent of residual immune activation/inflammation and (iii) the size of th persistent HIV reservoir during ART. These questions are highly relevant to people living with HIV (PLHIV) because targeting specific CD4 T cell subsets could be a potential priority to cure HIV infection. CD4 Central Memory T cells (TCM) are long-lived, self-renewing cells with a crucial role for CD4 T cell homeostasis and overall immune function. Recent evidence generated in nonhuman primate models of HIV infection implicates the infection of CD4 TCM as a key factor determining the outcome of infection. In the pathogenic SIV-infection of rhesus macaques, the levels of infection and depletion of CD4 TCM dictate the tempo of progression to AIDS, and the preservation of CD4 TCM in vaccinated animals associates with resistance to SIV infection. Furthermore, in nonpathogenic SIV infection of sooty mangabeys, a low level of CD4 TCM infection is a key mechanism of AIDS resistance. Consistent with the importance of preserving TCM from infection and with the findings that TCM have a longer half-life than TEM, we showed that in PLHIV on ART CD4 TCM represent the largest reservoir of infected CD4 T cells. Based on these findings, we propose a novel, paradigm-shifting model according to which the pattern of infected CD4 T cells is more important than the overall level of immune activation, virus replication, and the total number of infected cells in dictating the magnitude of CD4 T cell reconstitution and the size of the virus reservoir during ART. Here, we will test the hypotheses that, in blood and lymph nodes, CD4 TCM infection (i) critically contributes to the extent of immunologic restoration and residual immune activation [Aim 1] and (ii) is a prognostic factor for both the size and stability of the HIV reservoir [Aim 2] following ART. In addition, we are proposing a series of mechanistic studies aimed at defining the molecular correlates of CD4 TCM infection and designing therapeutic intervention that can protect these cells from infection [Aim 3]. We believe the proposed research is highly relevant to human health. By testing a radically innovative hypothesis, these studies will provide unprecedented, novel insights into the mechanism underlying the quality of the immunological response to ART and the resulting size/persistence of the HIV reservoir in PLHIV. If our hypothesis is confirmed, these studies will suggest that novel strategies aimed at protecting CD4 TCM from infection should be a critical component of interventions aimed at curing HIV infection.