# Characterizing the therapeutic efficacy of CD8 T cell responses induced by the IL-15 superagonist ALT-803

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2020 · $753,235

## Abstract

PROJECT SUMMARY
We do not have a vaccine or a cure for HIV. CD8 T cells are necessary for initial control of HIV viremia,
but attempts to design a CD8 T cell based HIV vaccine have been met with challenges. These include
(1) eliciting cellular immune responses against the most immunogenic regions of HIV and (2) enhancing
the function of antiviral immune responses at the right location to contain virus replication.
This proposal is a renewal of our original R01 testing the hypothesis that CD8 T cells targeting invariant
epitopes are unable to detect and destroy virally-infected cells. Based on the data generated during the
grant period, we published 4 manuscripts, presented 4 oral abstracts, presented 7 poster abstracts, and
delivered 8 seminars. We found that SIV control was delayed and incomplete in the absence of CD8 T
cells targeting the most immunogenic regions of SIV. Without detecting effective CD8 T cells to
suppress SIV replication in animals with non-protective MHC alleles, our study raises questions over
the feasibility of designing a universal vaccine to elicit CD8 T cells targeting invariant epitopes.
During the last grant period and using funds from the previous R01, we also made the remarkable
observation that the immunomodulatory IL-15 superagonist ALT-803 could boost CD8 T cell function to
promote virus suppression in macaques that received prior vaccination, but not in vaccine-naïve
animals. The data gathered from these studies has laid the foundation for us to test the hypothesis that
that ALT-803 treatment enhances the antiviral function of vaccine-elicited memory CD8 T cells
by recruiting IL-15 responsive antigen-specific CD8 T cells to lymph nodes to kill infected target
cells. We will test this hypothesis by comparing ALT-803 mediated suppression of SIV in vaccine-
naïve and vaccinated macaques. We also propose to characterize the responding CD8 T cell
population to determine if ALT-803 enhanced memory CD8 T cells in the vaccinated animals exhibit
increased antiviral function that is associated with transcription signatures indicative of increased IL-15
signaling through the JAK/STAT pathway. Together these data will help identify the features of
functionally relevant antiviral CD8 T cells in animals with non-protective MHC alleles.
Our study is relevant because ALT-803 is being used in clinical trials as an anti-tumor and anti-viral
agent. We want to maximize the effect of ALT-803 so that it is used most effectively in these settings.
Certain studies of ALT-803 cannot be performed in humans, including the one that we have proposed.
We will specifically evaluate whether vaccination BEFORE SIV infection is necessary for ALT-803 to
elicit functionally active CD8 T cells AFTER SIV infection. This is a paradigm shifting approach for
vaccine research, because it places a value on prophylactic vaccination of immunocompetent
individuals so that interventions are effective in HIV+ immunocomprimised individuals.

## Key facts

- **NIH application ID:** 9827522
- **Project number:** 5R01AI108415-07
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** SHELBY L OCONNOR
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $753,235
- **Award type:** 5
- **Project period:** 2013-12-05 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9827522

## Citation

> US National Institutes of Health, RePORTER application 9827522, Characterizing the therapeutic efficacy of CD8 T cell responses induced by the IL-15 superagonist ALT-803 (5R01AI108415-07). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9827522. Licensed CC0.

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