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Enhancing pulmonary immune reconstitution and limiting viral persistence with IL-21 therapy in Mtb/SIV co-infection

Award Number: R01AI194937
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/11/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2031

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Enhancing pulmonary immune reconstitution and limiting viral persistence with IL-21 therapy in Mtb/SIV co-infection - ABSTRACT Tuberculosis (TB) remains a leading cause of mortality in people living with HIV (PLHIV), with 161,000 deaths in 2023 despite widespread use of combinatorial antiretroviral therapy (cART). Although cART effectively suppresses HIV replication, it does not eliminate the markedly elevated risk of Mycobacterium tuberculosis (Mtb) reactivation in co-infected individuals. This persistent susceptibility is thought to stem from incomplete immune reconstitution, including impaired TH1/TH17 balance, reduced CD4⁺ effector memory T (TEM) cells, and ongoing immune activation in the lung. Our preliminary studies in an established Mtb/SIV rhesus macaque model demonstrate that cART alone fails to restore IL-21 and STAT1 signaling, both critical for immune control of TB and HIV. IL-21, a pleiotropic cytokine produced by CD4⁺ T cells, regulates TH1 and TH17 responses and supports macrophage function. Prior work shows that IL-21-IgFc therapy in SIV-infected macaques is safe and preserves mucosal immunity. We propose that IL-21-IgFc, when administered during early cART, can enhance immune reconstitution, reduce viral persistence, and improve TB control. The central hypothesis of this study is that adjunctive IL-21-IgFc therapy will restore key immune pathways in the lung, limit viral reservoirs, and improve macrophage function—thereby preventing Mtb reactivation in SIV- infected macaques. To test this, we will pursue two specific aims: • Aim 1 will determine how IL-21-IgFc therapy during early cART impacts pulmonary immune reconstitution and Mtb-specific responses. We will assess T cell subsets, STAT1/STAT3 signaling, granuloma integrity, and transcriptional signatures using flow cytometry, scRNAseq, and spatial transcriptomics. Additionally, we will perform cross-species transcriptomic comparisons between NHP and human PBMCs from cART-treated and untreated cohorts to identify conserved immune signatures and pathways associated with protection or disease progression. • Aim 2 will evaluate the effect of IL-21-IgFc therapy on viral persistence and macrophage function. We will measure SIV reservoirs in lung tissue, quantify macrophage proliferation, and assess tissue pathology to determine the impact of IL-21 on HIV-associated innate immune dysfunction. Impact: These studies will elucidate mechanisms by which IL-21 enhances lung immunity and limits pathogen persistence in TB/HIV co-infection. Findings will guide development of IL-21-based immunotherapies, a promising host-directed strategy to improve outcomes in high-burden populations where TB and HIV remain syndemic.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $927,025 )
2026	2026	TEXAS BIOMEDICAL RESEARCH INSTITUTE	8715 W MILITARY DR	SAN ANTONIO	TX	78227	BEXAR	USA	Allergy and Infectious Diseases Research	000	1	5/12/2026	NEW	$927,025
														Subtotal = $927,025

Grand Total All Awards = $927,025

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Enhancing pulmonary immune reconstitution and limiting viral persistence with IL-21 therapy in Mtb/SIV co-infection

Award Number: R01AI194937

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/11/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2031

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