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Targeting Cytolytic Cells to Lymphoid Sites of HIV Persistence.

将溶细胞细胞靶向 HIV 持续存在的淋巴部位。

基本信息

批准号：
9292706
负责人：
MICHAEL MARCEL LEDERMAN
金额：
$ 49.24万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9292706
关键词：
Acquired Immunodeficiency Syndrome Address Affect Agonist Anatomy Animals Anti-Retroviral Agents Antiviral Agents Architecture Autopsy B-Lymphocytes Binding Biopsy Blood Blood Circulation Brain CD8B1 gene Caring Cells Chemistry Chronic Clinical Trials Complete Blood Count Complication Control Groups Development Dose Effector Cell Environment Evaluation Exposure to FDA approved Flow Cytometry Goals HIV HIV Infections Health Homeostasis Human Immune Immunohistochemistry Infection Inflammation Inflammatory Intervention Location Lung Lymphocyte Lymphoid Lymphoid Tissue Lymphopenia Lysophospholipids Macaca mulatta Methods Modeling Movement Mucous Membrane Natural Killer Cells Organ Patients Penetration Pharmaceutical Preparations Phase Phenotype Play Population Primates Regimen Research Research Personnel Residual state Role SIV Safety Serum Site Source Sphingosine-1-Phosphate Receptor Spleen Staining method Stains Study models T-Lymphocyte Testing Therapeutic Time Viral Viral reservoir Virus Virus Replication Work animal resource base cytotoxic design dosage experience in vivo indexing longitudinal design lymph nodes multiple sclerosis treatment nonhuman primate novel novel strategies novel therapeutics receptor rectal replication therapy response safety testing sphingosine 1-phosphate successful intervention

项目摘要

DESCRIPTION: One of the greatest therapeutic challenges in HIV research and care is the goal of viral eradication. Any strategy aimed at HIV eradication in chronic infection will need to address the persistence of virus in secondary lymphoid organs. Eradicating virus from these sites is complicated. Lymph nodes (LN) are rapidly infected in early infection, and maintain residual level of activation/inflammation during ART that may potentiate infection of susceptible cells to sustain the latent reservoir. LN are sites at which penetration of otherwise effective antiretroviral drugs appears limited. A third critical complication is that cytolytic effector T cels are typically excluded from LN by their movement across a concentration gradient of the lysophospholipid sphingosine-1 phosphate (S1P). As a result, lymphoid tissues that constitute critical sites of HIV persistence are relatively protected from HIV-specific cytolytic cells. Based on these findings, we propose a novel approach to retain cytolytic cells in lymphoid tissues by administration of the S1P receptor agonist FTY720. We hypothesize that sustained exposure to cytolytic cells will promote a more inflammatory LN environment, will accelerate the stochastic bursts of SIV replication that play a role in sustaining HIV reservoirs, and will allow cytolytic clls to recognize and destroy virus expressing cells directly in lymphoid tissues. We will test this model in the well-established model of SIV infection of rhesus macaques (RMs) using the S1P receptor agonist FTY720, a molecule approved by the FDA for the treatment of multiple sclerosis that blocks the interaction of S1P with its receptors and results in significant circulatng lymphopenia as a consequence of lymphocyte sequestration in LN. Crucial for this proposal, we developed a fully suppressive ART regimen for SIV-infected RMs, thus validating this model for studies of HIV eradication and cure. In the R21 phase of this proposal, we will assess the safety and activity of two different doses of FTY720 in retaining cytolytic cells in lymphoid tissues in ART-suppressed SIV-infected RMs. If successful, these studies will pave the way for the R33 phase, in which we will determine how FTY720 - at the dose showing the best activity/safety profile in the R21 studies - affects (i) antiviral cytotoxic responses and residual inflammation an (ii) HIV persistence in lymphoid tissues. The longitudinal design will allow analyses of blood, LN and rectal biopsies before and during FTY720 treatment. Elective necropsy after the last dose of FTY720 will give us the unprecedented opportunity to address the effects of FTY720 in many other anatomic locations including spleen, lung and brain.