Understanding Th-monocyte interactions in HIV infection

了解 HIV 感染中 Th-单核细胞的相互作用

基本信息

批准号：
10265323
负责人：
Catarina E Hioe
金额：
--
依托单位：
JAMES J PETERS VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-01 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10265323
关键词：
Address Adherence Affect Affinity Anti-Retroviral Agents Antibodies Antigen-Antibody Complex Antigen-Presenting Cells Apoptosis Bacteria Binding CCR5 gene CCR6 gene CD4 Positive T Lymphocytes CXCR4 gene Caring Cell Communication Cell physiology Cells Chronic Chronic Phase Coculture Techniques Data Dendritic Cells Development Disease Elements Epithelial Attachment Epitope spreading Epitopes Fc Receptor Frequencies Future Genital Genitalia Goals Gut Mucosa HIV HIV Antibodies HIV Antigens HIV Infections HIV-1 Homing Human immunodeficiency virus test Immune Immunologics In Vitro Infection Inflammation Mediators Interleukin-17 Interleukin-2 Intestines Macaca Major Histocompatibility Complex Mannose Measures Mediating Medical Methods Mucous Membrane Neutralization Tests Onset of illness Outcome Pathogenesis Pathogenicity Patients Peptides Peripheral Pharmaceutical Preparations Phase Play Polysaccharides Property Provider Proviruses Quality of life Recovery Reporting Role SIV Survival Rate System T-Cell Activation T-Cell Receptor T-Lymphocyte Testing Th1 Cells Time Tropism United States Vaccines Veterans Viremia Virion Virus Virus Diseases Virus Replication antiretroviral therapy cell type cytokine design experimental study fungus health management humanized mouse immunological synapse in vitro activity in vivo in vivo Model microbial microbicide monocyte mouse model novel strategies peripheral blood permissiveness prevent prophylactic receptor receptor binding response standard of care sugar transmission process viral transmission virus envelope

项目摘要

Project Summary/Abstract: More than 30 years after the discovery of HIV, there are still no vaccines or microbicides to prevent HIV infection. Antiretroviral therapy (ART) is successful in suppressing virus replication, but it does not clear the virus, offers only partial immunologic recovery, and requires lifelong adherence. A better understanding of basic HIV–host cell interactions is needed to develop new strategies to prevent HIV infection. This proposed study seeks to investigate the interplay of HIV with antigen-presenting cells (APCs) and helper CD4 T (Th) cells in the presence of anti-HIV antibodies (Abs) that retard virus spread to Th cells. CD4 Th cells are the main cell type infected by HIV, but not all Th cells are equally vulnerable. As compared with Th1 cells, Th17 cells are preferentially targeted by HIV, in part due to higher expression of HIV envelope (Env) receptors, including α4β7. Our recent studies showed that Th17 cells are also preferentially targeted by HIV transmitted from APCs. However, different outcomes arise from HIV interactions with Th cells and distinct APCs. HIV-exposed monocytes efficiently transmit virus to Th17 cells while stimulating Th proliferation, resulting in expansion in the number of infected Th17 cells. In contrast, virus transmission from HIV-exposed monocyte-derived dendritic cells (MDDCs) causes the number of Th17 cells to decline. Further, we observed that in the immunological synapses between Th cells and APCs, HIV Env enhances Th cell activation by acting like a co-stimulatory molecule. Th cells thus co-stimulated become more permissive to HIV infection. HIV Env is the key determinant that regulates virus transmission to Th cells and cellular activation of target Th cells. HIV transmission varies depending on Env co-receptor tropisms (CCR5 vs CXCR4) and is sensitive to interference by anti-Env Abs. HIV-induced enhancement of Th cell activation also is triggered by Env and suppressed by anti-Env Abs. On the basis of these findings, we propose to further investigate the HIV Env determinants influencing the efficiency of virus transmission from APCs to Th cells. Our hypothesis is that HIV utilizes the intimate cell-cell contact between APCs and Th cells to spread to Th cells and also to enhance Th cell activation, rendering them more permissive for virus replication, through the action of the virus Env. Therefore, anti-Env Abs, by forming immune complexes with HIV virions, may alter APC-Th cell interactions to blunt virus transmission and replication. To test these hypotheses, in Aim 1, we will define HIV Env determinants that are essential for efficient transmission from APCs to Th cells. Monocytes and MDDCs treated with HIV will be tested as APCs in a co- culture system to stimulate Th1 and Th17 cells and transmit viruses with distinct Envs. The Env variables to be evaluated include co-receptor usage, N-glycan sugar composition, and affinity for α4β7 and mannose-binding receptors. Aim 2 is to evaluate the ability of anti-Env Abs to retard virus transmission from APCs to Th cells. We will test neutralizing and nonneutralizing monoclonal Abs specific for distinct epitopes, and polyclonal Abs generated by Env epitope-targeted vaccines. Fc-mediated activities of the Abs will also be assessed. Finally, in Aim 3, we will test HIV transmission from APCs in vivo, using the humanized mouse model. Anti-Env Abs with inhibitory activity in vitro will also be evaluated in the mouse model. The proposed experiments will generate data to inform future development of more effective prophylactic agents against HIV.

项目摘要/摘要： HIV 发现 30 多年后，仍然没有疫苗或杀菌剂来预防 HIV 抗逆转录病毒疗法（ART）可以成功抑制病毒复制，但不能清除感染。病毒，只能提供部分免疫恢复，并且需要终生坚持。需要基本的艾滋病毒与宿主细胞相互作用来制定预防艾滋病毒感染的新策略。研究旨在调查 HIV 与抗原呈递细胞 (APC) 和辅助 CD4 T (Th) 的相互作用细胞中存在抗 HIV 抗体 (Abs)，可阻止病毒传播至 Th 细胞。 CD4 Th 细胞是 HIV 感染的主要细胞类型，但并非所有 Th 细胞都同样脆弱。与 Th1 细胞相比，Th17 细胞优先成为 HIV 的攻击目标，部分原因是 HIV 表达较高包膜 (Env) 受体，包括 α4β7，我们最近的研究表明 Th17 细胞也优先。然而，HIV 与 Th 细胞的相互作用会产生不同的结果。和不同的 APC 暴露于 HIV 的单核细胞可有效地将病毒传播至 Th17 细胞，同时刺激 Th。增殖，导致受感染的 Th17 细胞数量增加，相反，病毒传播。暴露于 HIV 的单核细胞衍生树突状细胞 (MDDC) 会导致 Th17 细胞数量下降。我们观察到，在 Th 细胞和 APC 之间的免疫突触中，HIV Env 增强了 Th 细胞通过像共刺激分子一样进行激活，因此共刺激的 Th 细胞变得更容易受到 HIV 的影响。感染。 HIV Env 是调节病毒向 Th 细胞传播和靶标细胞激活的关键决定因素 Th 细胞的 HIV 传播取决于 Env 共同受体的趋向性（CCR5 与 CXCR4），并且对抗 Env 抗体的干扰也由 Env 和 HIV 诱导的 Th 细胞活化增强所触发。根据这些发现，我们建议进一步研究 HIV Env。影响病毒从 APC 传播到 Th 细胞的效率的决定因素是 HIV。利用 APC 和 Th 细胞之间的密切细胞接触传播到 Th 细胞并增强 Th 通过病毒 Env 的作用，细胞被激活，使它们更容易病毒复制。因此，抗 Env Abs 通过与 HIV 病毒体形成免疫复合物，可能会改变 APC-Th 细胞的相互作用，从而削弱病毒的传播和复制。为了检验这些假设，在目标 1 中，我们将定义 HIV Env 决定因素，这些决定因素对于有效从 APC 到 Th 细胞的传播将在联合测试中作为 APC 进行测试。培养系统刺激 Th1 和 Th17 细胞并传播具有不同环境变量的病毒。评估的内容包括辅助受体的使用、N-聚糖糖组成以及对 α4β7 和甘露糖结合的亲和力目标 2 是评估抗 Env 抗体阻止病毒从 APC 传播到 Th 细胞的能力。我们将测试针对不同表位的中和性和非中和性单克隆抗体以及多克隆抗体最后，还将评估由 Env 表位靶向疫苗产生的 Fc 介导的抗体活性。目标 3，我们将使用带有抗 Env 抗体的人源化小鼠模型，在体内测试 APC 的 HIV 传播。体外抑制活性也将在小鼠模型中进行评估。数据为未来开发更有效的艾滋病毒预防剂提供信息。