# Controlling HIV latency by manipulating CycT1 turnover

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $398,360

## Abstract

Abstract
Immune dysfunction associated with co-infection and AIDS-related cancers is commonly observed in
HIV-infected individuals. In particular, gene expression programs in the immune system are often
abnormally regulated in these individuals. We and other groups have recently discovered that the
positive transcription factor b (P-TEFb), a critical cellular factor required for productive elongation of
transcription, is severely down-regulated in quiescent and aberrant T cells. In resting CD4+ T cells,
representing major latent HIV reservoirs, the expression of the cyclin T1 (CycT1) subunit of P-TEFb is
diminished post-transcriptionally via currently unknown mechanisms, this being a main cause of HIV
latency and tumor-specific T cells' defective response to check-point inhibitors and/or CAR-T cell
therapies. Since increasing CycT1 is a prerequisite and mandatory step for optimal HIV reactivation
and proper immune response against other pathogens and tumor cells, understanding the
mechanism of CycT1 down-regulation is crucial. We have recently demonstrated that P-TEFb
assembly regulated by phosphorylation determines the stability of CycT1. Also, we have identified all
key players, including E3 ligases, involved in CycT1-degradation. Therefore, we hypothesize that
increasing CycT1 proteins in resting and aberrant CD4+ T cells by manipulating cellular pathways to
regulate P-TEFb assembly will reverse HIV latency and improve immune functions in HIV-infected
individuals. In the proposed study, we will manipulate the cellular pathways regulating P-TEFb
assembly and CycT1 stability to control HIV latency and improve immune functions. We will also
identify previously uncharacterized "CycT1-degradation complexes", which will serve as new
therapeutic targets. Successful completion of the proposed study will result in a new concept of T cell
regulation modulated by the protein level of a master transcriptional regulator.

## Key facts

- **NIH application ID:** 10680481
- **Project number:** 5R01AI167778-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Koh Fujinaga
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $398,360
- **Award type:** 5
- **Project period:** 2022-08-09 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10680481

## Citation

> US National Institutes of Health, RePORTER application 10680481, Controlling HIV latency by manipulating CycT1 turnover (5R01AI167778-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10680481. Licensed CC0.

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