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: 9124732
• 负责人: Vincent Charles Marconi
• 金额: $ 86.91万
• 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 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9124732
• 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; Immune system; Immunologics; In Vitro; Individual; Infection; Inflammation; Intervention; Life; Longevity; Macaca mulatta; Maintenance; Measures; Memory; Modeling; Molecular; Outcome; Pathogenesis; Pathway interactions; Pattern; Predisposition; Prognostic Factor; Research; Residual state; Resistance; Rest; Role; SIV; Series; Signal Pathway; T memory cell; T-Cell Activation; 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; 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.

产品说明：治愈HIV感染的一个主要障碍是我们不完全了解哪些因素调节抗逆转录病毒治疗（ART）的免疫反应以及潜伏HIV库的建立和持续存在。虽然已经确定HIV优先感染记忆性CD 4 T细胞，但仍不清楚HIV感染在各种CD 4 T细胞亚群中的相对分布是否以及在多大程度上影响：（i）CD 4 T细胞重建的幅度，（ii）残余免疫活化/炎症的程度，和（iii）这些问题与HIV感染者（PLHIV）高度相关，因为靶向特定的CD 4 T细胞亚群可能是治愈HIV感染的潜在优先事项。CD 4中央记忆T细胞（TCM）是长寿的自我更新细胞，对CD 4 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暗示CD 4 TCM感染是决定感染结果的关键因素。在致病性SIV感染的恒河猴中，感染水平和CD 4 TCM的消耗决定了进展为AIDS的克里思，并且在接种疫苗的动物中CD 4 TCM的保留与对SIV感染的抗性相关。此外，在非致病性SIV感染的白眉猴中，低水平的CD 4 TCM感染是抵抗艾滋病的关键机制。与保护TCM免受感染的重要性以及TCM具有比TEM更长的半衰期的发现一致，我们表明在ART上的PLHIV中，CD 4 TCM代表受感染的CD 4 T细胞的最大库。基于这些发现，我们提出了一种新的范式转换模型，根据该模型，在决定ART期间CD 4 T细胞重建的幅度和病毒库的大小方面，受感染的CD 4 T细胞的模式比免疫激活、病毒复制和受感染细胞的总数的总体水平更重要。CD 4 TCM感染（i）对免疫恢复和残留免疫激活的程度有重要作用[目的1]，（ii）是ART后HIV储库大小和稳定性的预后因素[目的2]。此外，我们提出了一系列机制研究，旨在确定CD 4中医感染的分子相关性，并设计治疗干预，这些细胞不受感染[目的3]。我们相信这项研究与人类健康密切相关。通过测试一个根本创新的假设，这些研究将提供前所未有的，新的见解的免疫反应的质量ART和由此产生的规模/持久性的艾滋病毒水库PLHIV的机制。如果我们的假设得到证实，这些研究将表明，旨在保护CD 4 TCM免受感染的新策略应该是旨在治愈HIV感染的干预措施的关键组成部分。