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

中央记忆 CD4 T 细胞感染：ART 反应和 HIV 持续存在的关键作用

• 批准号: 9330766
• 负责人: Vincent Charles Marconi
• 金额: $ 85.4万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-20 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9330766
• 关键词: Acquired Immunodeficiency Syndrome; African; Animals; Anti-Retroviral Agents; Biological Preservation; Blood; CD4 Positive T Lymphocytes; Cells; Cercocebus atys; Frequencies; HIV; HIV Infections; Half-Life; Health; Homeostasis; Human; Immune response; Immunologics; In Vitro; Individual; Infection; Inflammation; Intervention; Longevity; Macaca mulatta; Maintenance; Measures; Memory; Modeling; Molecular; Outcome; Pathogenesis; Pathogenicity; Pathway interactions; Pattern; Pharmacology; Predisposition; Prognostic Factor; Refractory; Research; Residual state; Resistance; Rest; Role; SIV; Series; Signal Pathway; T memory cell; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic Intervention; Time; Vaccinated; Vaccines; Viral reservoir; Viremia; Virus Diseases; Virus Replication; antiretroviral therapy; base; design; differential expression; immune activation; immune function; immune system function; in vivo; innovation; insight; lymph nodes; memory CD4 T lymphocyte; nonhuman primate; novel; novel strategies; public health relevance; reconstitution; response; restoration; self renewing cell; survival prediction

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.

描述：治愈HIV感染的一个主要障碍是我们对哪些因素调节抗逆转录病毒疗法(ART)的免疫反应以及潜伏的HIV储存库的建立和持续不完全的了解。虽然众所周知，HIV感染主要感染记忆中的CD4T细胞，但目前尚不清楚HIV感染在不同CD4T细胞亚群中的相对分布是否以及在多大程度上影响：(I)CD4T细胞重建的幅度，(Ii)残留免疫激活/炎症的程度，以及(Iii)ART期间持久HIV储存库的大小。这些问题与艾滋病毒携带者(PLHIV)高度相关，因为靶向特定的CD4T细胞亚群可能是治愈艾滋病毒感染的潜在优先事项。CD_4中央记忆T细胞是一种长寿、自我更新的细胞，对CD_4 T细胞的稳态和整体免疫功能起着至关重要的作用。最近在非人类灵长类动物HIV感染模型中产生的证据表明，CD4中医感染是决定感染结果的关键因素。在恒河猴病原性SIV感染过程中，感染和耗尽的程度决定了向艾滋病进展的速度，而免疫动物体内对SIV感染的抵抗力与其对CD4的保存有关。此外，在煤烟中非致病性SIV感染中，低水平的CD4中医感染是抵抗艾滋病的一个关键机制。与保护中医药免受感染的重要性以及中医药的半衰期比透射电子显微镜更长的发现相一致，我们表明在抗逆转录病毒治疗的PLHIV中，中医药是受感染的CD4T细胞的最大储存库。基于这些发现，我们提出了一个新的范式转换模型，根据该模型，在ART期间，感染的CD4T细胞的模式比免疫激活的总体水平、病毒复制和感染细胞的总数更重要，这决定了CD4T细胞重建的幅度和病毒库的大小。在这里，我们将检验这样的假设：在血液和淋巴结中，CD4中医感染(I)对免疫恢复和残余免疫激活的程度起关键作用[目标1]和(Ii)是接受抗逆转录病毒治疗后艾滋病毒储备库的大小和稳定性的预测因素[目标2]。此外，我们还提出了一系列机制研究，旨在确定CD4中医感染的分子相关性，并设计能够保护这些细胞免受感染的治疗干预措施[目标3]。我们相信，这项拟议的研究与人类健康高度相关。通过测试一种全新的假说，这些研究将提供前所未有的、新颖的见解，揭示抗逆转录病毒药物的免疫反应质量的潜在机制，以及由此产生的艾滋病病毒在PLHIV中的储存大小/持久性。如果我们的假设得到证实，这些研究将表明，旨在保护CD4中医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。