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.

描述：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 病毒库的建立和持续。尽管已明确 HIV 优先感染记忆 CD4 T 细胞，但仍不清楚 HIV 感染在各种 CD4 T 细胞亚群中的相对分布是否以及在何种程度上影响：(i) CD4 T 细胞重建的程度，( ii) 残余免疫激活/炎症的程度以及 (iii) ART 期间持续存在的 HIV 病毒库的大小。这些问题与 HIV 感染者 (PLHIV) 高度相关，因为针对特定 CD4 T 细胞亚群可能是治愈 HIV 感染的潜在优先事项。 CD4 中央记忆 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至关重要。最近在 HIV 感染的非人灵长类动物模型中产生的证据表明，CD4 TCM 的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，CD4中药的感染水平和消耗决定了艾滋病进展的速度，并且接种疫苗的动物中CD4中药的保留与对SIV感染的抵抗力相关。此外，在乌白眉猴的非致病性SIV感染中，低水平的CD4 TCM感染是艾滋病抵抗的关键机制。与保护 TCM 免受感染的重要性以及 TCM 比 TEM 的半衰期更长的发现一致，我们表明，在 ART CD4 TCM 上的 PLHIV 中，TCM 代表了受感染 CD4 T 细胞的最大储存库。基于这些发现，我们提出了一种新颖的范式转换模型，根据该模型，受感染的 CD4 T 细胞的模式比免疫激活的总体水平、病毒复制和受感染细胞的总数更重要，从而决定了感染的程度。 ART 期间 CD4 T 细胞重建和病毒库的大小。在这里，我们将测试以下假设：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有重要贡献 [目标 1] 和 (ii) 是大小和淋巴结的预后因素ART 后 HIV 储存库的稳定性 [目标 2]。此外，我们提出了一系列机制研究，旨在明确 CD4 TCM 感染的分子相关性，并设计可以保护这些细胞免受感染的治疗干预措施 [目标 3]。我们相信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 ART 免疫反应质量的潜在机制以及由此产生的 PLHIV 中 HIV 病毒库的大小/持久性提供前所未有的新颖见解。如果我们的假设得到证实，这些研究将表明旨在保护 CD4 中药免受感染的新策略应该成为旨在治愈 HIV 感染的干预措施的关键组成部分。