Exploration into the Forgotten HIV Reservoir with Models of HIV/SIV Persistence in Mucosal Tissues

利用粘膜组织中 HIV/SIV 持续存在的模型探索被遗忘的 HIV 病毒库

• 批准号: 10666594
• 负责人: Jeremy A O'Sullivan
• 金额: $ 48.84万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10666594
• 关键词: Active Sites; Address; Adherence; Area; Autopsy; Binding; Biological Assay; Blood; CD4 Positive T Lymphocytes; Cell Separation; Cells; Cessation of life; Chronic Disease; Collaborations; Colon; Connective Tissue; Data; Development; Epidemic; Frequencies; Generations; Genetic Transcription; Goals; Greater sac of peritoneum; Gut Mucosa; HIV; HIV Infections; Human; Immune; Immune system; In Vitro; Individual; Infection; Interruption; Intervention; Longevity; Lymphocyte; Macaca; Macrophage; Modeling; Mucous Membrane; Myelogenous; Myeloid Cells; Nature; Neuroimmune system; PET/CT scan; Pathogenesis; Patients; Peripheral; Persons; Phenotype; Play; Predisposition; Research Personnel; Resources; Role; SIV; Sampling; Signal Transduction; Site; Skin; Stimulus; Study models; T-Lymphocyte; Techniques; Technology; Testing; Time; Tissues; Toxic effect; Viral; Virus; Virus Replication; antiretroviral therapy; cell type; cost; design; forgetting; granulocyte; humanized mouse; in vivo; in vivo Model; innovation; insight; lymph nodes; mast cell; mouse model; mucosal site; nonhuman primate; nonhuman tissue; novel; progenitor; response; tool; viral rebound

PROJECT SUMMARY/ABSTRACT For many HIV infected people, lifelong combination antiretroviral therapy (cART) has converted the HIV epidemic from death sentence into a manageable chronic disease. However, the HIV reservoir persists in all treated individuals and viral rebound occurs upon cART interruption in the vast majority of patients. Given the challenges related to lifelong cART treatment such as adherence, viral escape, toxicity, and costs, finding novel ways to eradicate the virus and/or induce sustained virologic control in absence of cART is a very high priority in the HIV field. Tissues are major sites for HIV latency and notable contributors to viral rebound after cART interruption. Our preliminary data demonstrate that SIV infected mast cells (MC), a type of granulocyte derived from myeloid progenitors may have an important, albeit understudied role in the persistence of HIV in tissues. MC contribute to both the immune and neuroimmune systems and reside almost exclusively in connective tissues and skin. Hence, until now the study of HIV infection of MC and their potential role in HIV reservoir has been thwarted by logistical difficulties in both isolating these cells and identifying rare foci of HIV/SIV infection in tissues especially during therapy. The technological advancements of our team led to the identification of SIV infected MC at the time of rebound after antiretroviral treatment interruption in macaques. This, in turn, led to ex vivo studies and the generation of preliminary data by a team of investigators with expertise in both HIV and MC. Our preliminary data strongly support a role of tissue MC in HIV pathogenesis and persistence. These tissue resident cells live much longer than lymphocytes and susceptible to infection at least in a way that it is comparable to CD4+ T cells. Hence, we propose to use a variety of unique tools and resources to explore the dynamics of HIV infection ex vivo and address the hypothesis that HIV infected MC play an important role in the HIV tissue reservoir. Specifically, we will use tissues from non-human primate studies (Aim 1) that will be collected via PET-CT-guided sampling from areas identified with active SIV expression. We will characterize the frequency of infected CD4+ T cells and MCs in these areas during different types of interventions. We will use ex vivo and in vitro infection (Aim 2) of human gut and skin derived MC to understand the dynamics of HIV infection and persistence and the impact of different stimuli on HIV replication in presence and absence of cART. Finally, we will use a humanized mouse model of MC (Aim 3) to investigate questions similar to those addressed by Aim 2 either in vivo or ex vivo. In summary, we will leverage a toolbox of different and complementary models and techniques to address the role of tissue MC in contributing to HIV persistence and to determine how to manipulate and target this “forgotten” reservoir to facilitate the development of novel, more comprehensive HIV cure strategies.

项目总结/文摘