Abstract
The persistence of HIV-1 in long-lived latent reservoirs during suppressive antiretroviral therapy (ART) remains one of the principal barriers to a functional cure. Blocks to transcriptional elongation play a central role in maintaining the latent state, and several latency reversal strategies focus on the release of positive transcription elongation factor b (P-TEFb) from sequestration by negative regulatory complexes, such as the 7SK complex and BRD4. Another major cellular reservoir of P-TEFb is in Super Elongation Complexes (SECs), which play broad regulatory roles in host gene expression. Still, it is unknown if the release of P-TEFb from SECs is a viable latency reversal strategy. Here, we demonstrate that the SEC is not required for HIV-1 replication in primary CD4+ T cells and that a small molecular inhibitor of the P-TEFb/SEC interaction (termed KL-2) increases viral transcription. KL-2 acts synergistically with other latency reversing agents (LRAs) to reactivate viral transcription in several cell line models of latency in a manner that is, at least in part, dependent on the viral Tat protein. Finally, we demonstrate that KL-2 enhances viral reactivation in peripheral blood mononuclear cells (PBMCs) from people living with HIV (PLWH) on suppressive ART, most notably in combination with inhibitor of apoptosis protein antagonists (IAPi). Taken together, these results suggest that the release of P-TEFb from cellular SECs may be a novel route for HIV-1 latency reactivation.
Original language | English (US) |
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Article number | e1012083 |
Journal | PLoS pathogens |
Volume | 20 |
Issue number | 9 |
DOIs | |
State | Published - Sep 2024 |
Funding
This research was supported by NIH/ NIAID funding for the HIV Accessory & Regulatory Complexes (HARC) Center (U54 AI170792, J.F.H.), Northwestern University Cell and Molecular Basis of Disease (CMBD) Training Program (T32 GM008061, W.J.C.), NIH funding for the Third Coast Center for AIDS Research (P30 AI117943, J. F.H. and R.L.R), NIH/NIAID grants for HIV research (R01AI176599, R01AI167778, R01AI150455, R01AI165236, R01AI150998, and R21AI174864 to J.F.H.; R01MH125778 and P01AI169600 to R.L.R). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We would like to thank members of the Hultquist Lab for comments, manuscript revision, and helpful discussions. We would like to thank Cristina Vaca and the laboratory of Dr. Richard T. D\u2019Aquila (Northwestern University) for sharing the J-Lat 6.3 and J-Lat 11.1 cell lines. Additionally, we would like to thank Dr. Elena Martinelli (Northwestern University) for sharing the U1 cell line and Dr. Mojgan Naghavi (Northwestern University) for sharing the CHME3-4x4 cell line.
ASJC Scopus subject areas
- Parasitology
- Microbiology
- Immunology
- Molecular Biology
- Genetics
- Virology