# Modulating Immune Senescence of Effector Lymphocytes in Chronic HIV Infection

> **NIH NIH R03** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2020 · $114,375

## Abstract

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...

## Key facts

- **NIH application ID:** 9990643
- **Project number:** 5R03AG060192-02
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Adam Mitchell Spivak
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $114,375
- **Award type:** 5
- **Project period:** 2019-08-15 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9990643

## Citation

> US National Institutes of Health, RePORTER application 9990643, Modulating Immune Senescence of Effector Lymphocytes in Chronic HIV Infection (5R03AG060192-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9990643. Licensed CC0.

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