# CTL-Mediated Elimination of Replication Competent vs. Defective HIV Proviruses from Natural Latent Reservoirs: Roles of Antigen Specificity and Functional Characteristics

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2021 · $423,750

## Abstract

Although modern therapies have improved the outlooks for people living with HIV/AIDS
(PLWHA) they are unable to cure infection, leaving these individuals burdened by a
lifelong commitment to expensive antiretroviral medication. It has also become clear that
these treatments do not fully restore health, nor do they address the negative social
issues associated with being HIV positive. The development of a safe and effective HIV
cure would thus greatly improve the lives of PLWHA. A major obstacle to curing HIV
infection is the establishment of reservoirs of hidden or ‘latent’ virus which evade the
immune system and can re-seed infection if an individual stops antiretroviral therapy.
Efforts are underway to attempt to purge these HIV reservoirs. There is theoretically
achievable by combining ‘latency reversing agents’ (LRAs) capable of exposing hidden
virus with immune effectors such as killer T-cells that can then eliminate these cells, the
so-called ‘shock and kill’ approach. The viability of the shock and kill strategy is
supported by in vitro experiments using cell line models of latency, where combinations
of LRAs with killer T-cells can reduce HIV reservoirs. However, clinical trials that have
attempted to achieve this in vivo have yielded disappointing results. In preliminary
studies, we have attempted to bridge this gap by determining if combinations of LRAs
with killer T-cells could eliminate HIV from patient CD4+ T-cell samples in vitro. We made
the surprising observation that this consistently resulted in the elimination of the
defective HIV proviruses that make up the majority of HIV DNA, without impacting the
intact inducible proviruses that need to be eliminated to cure infection. In the current
project we propose the testing of different combinations of HIV-specific killer T-cells and
LRAs in this assay, in the hopes of identifying combinations that are able to more
effectively target intact inducible proviruses. Our study design will allow us to identify
general features of both killer T-cells and of LRAs that are associated with effective
elimination of intact inducible proviruses. In the process of perturbing these natural HIV
reservoirs, we will also test a wide range of reservoir measurement assays to determine
which best reflect depletions in intact inducible proviruses versus of total/defective
proviruses. Our study will thus provide critical guidance both for the design of
interventions aimed at curing HIV infection in future clinical trials, and for the selection
and interpretation of reservoir measurement assays to be used in these studies.

## Key facts

- **NIH application ID:** 10219055
- **Project number:** 5R01AI131798-05
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** R. Brad Jones
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $423,750
- **Award type:** 5
- **Project period:** 2018-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10219055

## Citation

> US National Institutes of Health, RePORTER application 10219055, CTL-Mediated Elimination of Replication Competent vs. Defective HIV Proviruses from Natural Latent Reservoirs: Roles of Antigen Specificity and Functional Characteristics (5R01AI131798-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10219055. Licensed CC0.

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