# Targeting PD-1 Pathway for Functional Cure of AIDS

> **NIH NIH R01** · EMORY UNIVERSITY · 2024 · $928,498

## Abstract

This proposal aims to develop an effective therapy to achieve HIV remission by improving the magnitude,
breadth, and function of anti-viral CD8 T cells and reducing viral reservoirs using the SIV/macaque model.
Dysfunctional anti-HIV immunity and the persistence of viral reservoirs represent two major issues that must be
addressed by therapeutic approaches targeting functional cure for HIV. We believe that these two issues can be
addressed effectively using a combination of vaccination and inhibiting the programmed death-1 co-inhibitory
pathway (PD-1 blockade). Accordingly, during the past 9 years of this R37, we invested major efforts to
comprehensively define the influence of the timing of PD-1 blockade at different stages of chronic SIV infection
and during anti-retroviral therapy (ART) on restoring CD8 T cell function and diminishing viral reservoirs. We also
tested the influence of combining PD-1 blockade with vaccination. These results showed that a combination of
therapeutic vaccination under ART and PD-1 blockade post analytical treatment interruption (ATI) leads to a
profound control of reemerging viremia with some animals suppressing viremia to below the level of detection
for up to 24 weeks. These results demonstrated the utility of this combination approach towards achieving HIV
remission. Our recent data in mice showed that the addition of IL-2 cytokine therapy to PD-1 blockade markedly
enhances the induction of highly functional effector cells and modulates their differentiation program leading to
better control of LCMV infection. Based on these exciting results, we propose to improve the therapeutic potential
of PD-1 blockade by combining it with IL-2 cytokine therapy. We propose 3 specific aims. In Aim 1, we will
determine the safety and therapeutic efficacy of a combination of PD-1 blockade and IL-2 cytokine therapy post
ATI in SIV infected and vaccinated macaques. In Aim 2, we will define the heterogeneity of exhausted CD8 T
cells during chronic SIV infection and define how PD-1 blockade with and without IL-2 will modify the T cell
exhaustion program. In Aim 3, we will test if an improved therapeutic vaccine combined with PD-1 blockade plus
IL-2 therapy can enhance control of reemerging SIV viremia. This will be a collaborative effort between Amara
(Emory), Ahmed (Emory), and Freeman (Harvard) laboratories. All three labs have worked together for over 15
years to optimize the PD-1 blockade to treat chronic SIV infection. By the completion of these aims, we hope to
develop potent immunotherapy to achieve profound and sustained control of SIV infection in the absence of ART
therapy.

## Key facts

- **NIH application ID:** 10839059
- **Project number:** 2R01AI112787-11
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Rama Rao Amara
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $928,498
- **Award type:** 2
- **Project period:** 2014-02-01 → 2028-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10839059

## Citation

> US National Institutes of Health, RePORTER application 10839059, Targeting PD-1 Pathway for Functional Cure of AIDS (2R01AI112787-11). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10839059. Licensed CC0.

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