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Immune based interventions for HIV eradication

基于免疫的干预措施消灭艾滋病毒

基本信息

批准号：
9010930
负责人：
Mirko Paiardini
金额：
$ 87.78万
依托单位：
EMORY UNIVERSITY
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：
2015-02-06 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9010930
关键词：
Acquired Immunodeficiency Syndrome Acute Affect Animal Model Animals Anti-Retroviral Agents Antibodies Antiviral Agents Antiviral Response Automobile Driving Blood CD4 Positive T Lymphocytes CD8B1 gene Cell Maintenance Cells Chronic Clinical Clinical Management Clinical Trials Combined Modality Therapy Consensus Data Defensins Development Disease Epithelial Equilibrium FDA approved Goals HIV HIV Infections Health Homeostasis Human Immune Immune System Diseases Immune response Individual Infection Inflammation Interferon Type I Interferon-alpha Interferons Interruption Intervention Intestines Lead Macaca mulatta Mediating Memory B-Lymphocyte Modeling Molecular Natural Killer Cells Organ Plasma Cells Primates Proteins Regimen Regulatory T-Lymphocyte Research Residual Tumors Residual state SIV Safety Series T-Lymphocyte T-Lymphocyte Subsets Testing Therapeutic Tight Junctions Tissues Viral reservoir Virus Virus Diseases Virus Replication animal resource base cost cytokine exhaustion experience global health human disease immune function improved in vivo interleukin-21 novel novel strategies novel therapeutics pre-clinical premature reconstitution response senescence

项目摘要

DESCRIPTION (provided by applicant): Despite many major advances in AIDS research, including the development and optimization of potent anti- retroviral therapy (ART) that successfully suppresses virus replication in the majority of HIV-infected individuals, a treatment that can cure this deadly infection is still not available. Residual disease in ART-treated HIV-infected individuals consists mainly of (i) persistent immune abnormalities (including inflammation, limited CD4 T cell reconstitution, and premature immune senescence) which may ultimately lead to the so-called "HIV- associated end-organ diseases", and (ii) the presence of persistent reservoirs of latently infected cells that are not affected by ART and are responsible for the rapid rebound of virus replication if ART is stopped. In the absence of a scalable treatment able to cure HIV infection, ART is a lifelong treatment that poses significant challenges in terms of costs and clinical safety. For these reasons, eradicating or at least functionally curing HIV infection would have a remarkable impact on global health. Residual inflammation may promote HIV persistence under ART by several mechanisms, including driving the infection of susceptible cells that sustain the persistence of the reservoir, and the exhaustion of HIV-specific antiviral immune responses. Thus, a vicious cycle may be triggered in which residual inflammation, ineffective antiviral immune responses, and HIV persistence are intimately connected. As such, there is a strong consensus that a cure for HIV infection will not be achieved through ART intensification alone, and that novel approaches aimed at limiting residual inflammation and improving antiviral immune responses may be needed. The overarching goal of this project is to explore the therapeutic potential of a novel, combined Interleukin (IL)-21 and Interferon-a (IFNa) intervention in ART-treated SIV-infected rhesus macaques (RMs). We propose that the sequential administration of IL-21 and IFNa is safe and will have a strong synergistic effect on HIV persistence by decreasing immune dysfunction and inflammation (via IL-21), as well as enhancing antiviral functions mediated by a number of host restriction factors (via IFNa). These hypotheses will be tested in Aims 1 and 2. Moreover, we are proposing a series of mechanistic studies aimed at defining the molecular and cellular effects of sequential administration of IL-21 and IFNa [Aim 3]. If our hypothesis is correct, the proposed studies will provide in vivo evidence of reduced inflammation, improved immune function, and decreased virus reservoirs following sequential IL-21 and IFNa treatment in the most relevant preclinical animal model of HIV infection and using two molecules that, as a single agent, are being tested (IL-21) or approved by the FDA (IFNa) for treatment of several human diseases. If successful, the proposed immune based intervention would then be tested in human clinical trials to assess its potential as a functional cure for HIV infection.