Modulating Immune Senescence of Effector Lymphocytes in Chronic HIV Infection
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PROJECT SUMMARY / ABSTRACT Combination antiretroviral therapy (ART) has transformed HIV-1 infection from an untreatable, lethal condition into a manageable medical problem. However, the immune system does not return to full fitness despite the restoration of the CD4+ T cell compartment and durable suppression of viremia by ART. Immune effector cells (CD8+ T cells and NK cells) of HIV-1-infected individuals on chronic ART demonstrate a phenotype of immune exhaustion. Treated HIV-1 infection is associated with significant risk of age-related diseases, including cardiovascular disease (CVD). Persistent immunological abnormalities paired with clinical observations of increased morbidity and mortality have led to recognition that treated HIV-1 resembles a state of accelerated immunological aging. This has multiple potential causes, including the degree of immune dysregulation caused by HIV-1 infection prior to treatment, the persistence of virus in cellular reservoirs despite ART, and indefinite ART administration itself. Understanding the relative contribution of these factors will be critical to improve outcomes for the growing population of aging HIV-1-positive patients. The mechanistic target of rapamycin (mTOR) is a kinase active in innate and adaptive immune cells that governs cellular metabolism, growth and survival. While the mTOR inhibitor rapamycin is FDA-approved and widely used for chronic immune suppression in organ transplant recipients, this drug at lower dosing has been shown to be immune-stimulatory, boosting both anti-pathogen and anti-tumor responses. Furthermore, HIV-1-positive kidney transplant recipients treated with rapamycin were found to have smaller HIV-1 reservoirs than those taking other immunomodulatory agents, suggesting a possible role of mTOR signaling in regulating viral persistence. These lines of evidence identify mTOR signaling as a high yield target to ameliorate the immunologic dysfunction of chronic, treated HIV-1 infection. This application proposes experiments to modulate the anti-viral function and perivascular inflammation induced by effector lymphocytes through mTOR inhibition. Despite the suppression of viral replication by ART and consequent improvement in mortality, it has become clear that immunologic dysregulation persists in the form of chronic immune activation and immunologic aging in HIV-1-infected ART-treated patients. The importance of understanding the mechanisms leading to immunosenescence and serious pathophysiologic consequences including cardiovascular disease in treated HIV-1 infection is underscored by the chronologic aging of the HIV-1 infected population in the United States. We propose hypothesis-driven experiments in order to evaluate the role of mTOR inhibition on the immunophenotype and function of circulating CD8+ T cells and NK cell subsets in the peripheral blood of treated HIV-1 infected individuals. Exploring the drivers of immunosenescence in treated HIV-1 infection will have therapeutic implications for HIV-1 infection and a multitude of aging-related disease states including CVD.
