Defining and Targeting the Adenosine-ADA-1 Axis in HIV-Specific CD8+ T Cell Dysfunction
NIAID - National Institute of Allergy and Infectious Diseases
About This Grant
Project Summary Antiretroviral therapy (ART) effectively suppresses HIV replication, yet treatment interruption results in rapid viral rebound due to persistent viral reservoirs. A major barrier to eliminating these reservoirs is the progressive loss of HIV-specific CD8+ T cell effector function. Although immune checkpoint blockade can partially restore T cell function in cancer, these approaches show limited efficacy in people living with HIV (PLWH), underscoring the need to identify alternative mechanisms contributing to HIV-specific CD8+ T cell dysfunction. Extracellular adenosine (ADO) is a potent immunosuppressive metabolite generated from inflammatory ATP by the ectonucleotidases CD39 and CD73 and signals through the A2a adenosine receptor to inhibit CD8+ T cell function. Under physiological conditions, ADO levels are tightly regulated by adenosine deaminase-1 (ADA-1). In PLWH, increased expression of ADO-generating enzymes and A2aR, together with reduced ADA-1 expression, promotes ADO accumulation and is associated with immune dysfunction. However, the contribution of the ADO/ADA-1 axis to antigen-specific CD8+ T cell impairment in PLWH remains poorly defined. This project will define the role of ADO signaling in HIV-specific CD8+ T cell dysfunction (Aim 1) and evaluate whether targeted ADA-1 supplementation can improve antiviral function (Aim 2). We hypothesize that ADO/ADA- 1 axis impacts antigen-specific CD8+T cell function in PLWH and that restoring ADA-1 activity will improve HIV- specific function. Aim 1 will quantify ADO-driven suppression of antigen-specific CD8+ T cell function in PLWH. Aim 1.1 will determine whether HIV-specific CD8+ T cells are more susceptible to ADO-mediated suppression than CMV-specific CD8+ T cells within the same donor. Preliminary data demonstrate epigenetic and transcriptional repression of ADA-1 and enhanced ADO-pathway signaling in HIV-specific CD8+ T cells, supporting increased vulnerability. Aim 1.2 will determine whether chronic HIV infection broadly increases ADO sensitivity by comparing antigen-specific CD8+ T cell responses from PLWH and HIV-negative donors. Established MDDC–T cell coculture assays will be used to model antigen-specific function ex vivo. Aim 2 will test whether targeted ADA-1 supplementation improves HIV-specific CD8+ T cell function. Building on preliminary feasibility data, ADA-1 mRNA will be delivered selectively to CD8+ T cells using CD8- targeted lipid nanoparticles, alone or in combination with PD-1 blockade, to assess functional improvement. Overall, this exploratory study will define a mechanistically distinct pathway contributing to HIV-associated CD8+ T cell dysfunction and evaluate ADA-1 supplementation as a targeted strategy to restore antiviral immunity, informing future immune-based HIV cure approaches.
Grant Summary
Defining and Targeting the Adenosine-ADA-1 Axis in HIV-Specific CD8+ T Cell Dysfunction is a NIAID - National Institute of Allergy and Infectious Diseases grant providing up to $250K for university, nonprofit, healthcare org. Applications are due 2028-06-30 (open). Check eligibility and apply with FindGrants.
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Eligibility
How to Apply
Up to $250K
2028-06-30
- 1Confirm your organization is eligible for Defining and Targeting the Adenosine-ADA-1 Axis in HIV-Specific CD8+ T Cell Dysfunction from NIAID - National Institute of Allergy and Infectious Diseases, checking organization type, location, and any population or project requirements.
- 2Gather the required documents and information, including your organization details, project plan, and budget figures.
- 3Draft your application narrative and budget addressing the funder's priorities and review criteria. FindGrants can draft each section for you to review and edit.
- 4Review every section against the requirements checklist, then export a submission-ready application pack and submit it to NIAID - National Institute of Allergy and Infectious Diseases before the deadline.
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Defining and Targeting the Adenosine-ADA-1 Axis in HIV-Specific CD8+ T Cell Dysfunction: Frequently Asked Questions
Who is eligible for the Defining and Targeting the Adenosine-ADA-1 Axis in HIV-Specific CD8+ T Cell Dysfunction?
Defining and Targeting the Adenosine-ADA-1 Axis in HIV-Specific CD8+ T Cell Dysfunction is offered by NIAID - National Institute of Allergy and Infectious Diseases and is generally open to university, nonprofit, healthcare org. It is open to organizations nationwide unless the funder specifies otherwise. Review the specific eligibility terms before applying, since funders set their own requirements around organization type, location, and the population or project being served.
How much funding does the Defining and Targeting the Adenosine-ADA-1 Axis in HIV-Specific CD8+ T Cell Dysfunction provide?
Defining and Targeting the Adenosine-ADA-1 Axis in HIV-Specific CD8+ T Cell Dysfunction provides up to $250K per award from NIAID - National Institute of Allergy and Infectious Diseases. Actual award sizes depend on the scope of your project, available program funds, and the number of applicants, so build a budget that reflects realistic, allowable costs rather than the maximum figure.
When is the Defining and Targeting the Adenosine-ADA-1 Axis in HIV-Specific CD8+ T Cell Dysfunction deadline?
Applications for Defining and Targeting the Adenosine-ADA-1 Axis in HIV-Specific CD8+ T Cell Dysfunction are due 2028-06-30 (open). Because deadlines can change, verify the date with the funder, NIAID - National Institute of Allergy and Infectious Diseases, and give yourself enough time to prepare a complete, competitive application before the close date.
How do you apply for the Defining and Targeting the Adenosine-ADA-1 Axis in HIV-Specific CD8+ T Cell Dysfunction?
To apply for Defining and Targeting the Adenosine-ADA-1 Axis in HIV-Specific CD8+ T Cell Dysfunction, confirm your eligibility, gather the required documents, and prepare a narrative and budget that address the funder's priorities. FindGrants guides you step by step and can draft each section, then exports a submission-ready application pack for this grant from NIAID - National Institute of Allergy and Infectious Diseases.