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Targeting latently infected Tfh cells to achieving a functional cure of HIV-1

靶向潜伏感染的 Tfh 细胞以实现 HIV-1 的功能性治愈

基本信息

批准号：
8892533
负责人：
Qigui Q Yu
金额：
$ 38.63万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-03-01 至 2020-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8892533
关键词：
Ablation Affect Affinity Antibodies Antiviral Agents Apoptosis B-Lymphocytes BCL6 gene BLR1 gene Back CD4 Positive T Lymphocytes Cell Line Cell Survival Cells DNA Data Development Disease Frequencies Generations Goals HIV HIV-1 Human Immune Immunity Immunoglobulin Class Switching In Vitro Infection Integral Membrane Protein Interferons Lead Life Life Cycle Stages Lymphocytic choriomeningitis virus Memory Molecular Mus Myxovirus Nuclear Nuclear Import Pathogenesis Patients Peptides Phase Population Predisposition Proviruses Research Resistance Rest Scientist Small Interfering RNA Structure of germinal center of lymph node Testing Th1 Cells Transcription Repressor/Corepressor Viral abstracting base cell type cohort in vivo inhibitor/antagonist insight killings large cell Diffuse non-Hodgkin&apos s lymphoma lymph nodes memory CD4 T lymphocyte new therapeutic target novel therapeutic intervention public health relevance

项目摘要

DESCRIPTION (provided by applicant): PROJECT SUMMARY/ABSTRACT CD4+ T cells are the major target for HIV-1 infection, and their loss is a hallmark of HIV-1 disease. However, follicular helper T (Tfh) cells, a distinct subset of CD4+ T cells that are specialized in helping B cells to form germinal centers (GCs) for generation of high-affinity class-switched antibodies, expand in patients chronically infected with HIV-1. The observed Tfh cell expansion is not due to a lower susceptibility of this cell type to HIV-1 infection, as Tfh cells have been identified as a major CD4+ T cell compartment for HIV-1 infection and replication. Why Tfh cells are more permissive of HIV-1 replication is unknown. Whether infected Tfh cells efficiently revert back to a resting memory state to become a major reservoir of HIV-1 latency is also unknown. We hypothesize that Tfh cells have weakened cell-intrinsic antiviral immunity, thereby rendering these cells more susceptible to HIV-1 replication. We also hypothesize that some infected Tfh cells survive and revert back to a resting memory state and become cellular reservoirs of HIV-1 latency. To pursue these hypotheses, we formed a research team consisting of four scientists with complementary expertise in cell-intrinsic immunity, Tfh cell development, HIV-1 pathogenesis, and therapy. We have Preliminary Data showing that (i) Tfh cells express significantly lower levels of cell-intrinsic anti-HIV-1 restricton factors including IFITM3 (interferon-induced transmembrane protein 3) and MX2 (myxovirus resistance 2) than other CD4+ T cell types, which may be attributed to the high constitutive expression of the transcriptional repressor BCL6 (B cell lymphoma 6) in Tfh cells, (ii) BCL6 controls development of memory CD4+ T cells, and (iii) BCL6 controls development of CXCR5+ Tfh cells in immunized mice. Based on these preliminary findings, we have three Specific Aims to determine: (1) whether Tfh cells have weakened cell-intrinsic anti-HIV-1 immunity (Aim 1), (2) the levels of IFITM3 and MX2 in Tfh versus non-Tfh CD4+ T cells from HIV-1 patients and their relationships with the frequency of latently- infected Tfh versus non-Tfh CD4+ T cells (Aim 2), and (3) whether BCL6 controls Tfh cell survival and whether abrogation of BCL6 function induces killing of the long-lived latently infected Tfh cells from HIV-1 patients (Aim 3). With the ultimate goal of defining and eliminating HIV-1 reservoirs in infected patients, we propose to take advantage of a large cohort of HIV-1 patients to identify and characterize cellular reservoirs in HIV-1 patients. Our results will provide insights into how HIV-1 latency is established and maintained, and may lead to new therapeutic interventions for a functional cure of HIV-1.