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Review 4: "Release of P-TEFb from the Super Elongation Complex promotes HIV-1 Latency Reversal"

Reviewers noted concerns including the high, toxic concentrations of the inhibitor used, lack of raw data and normalization details, and the need for further mechanistic evidence of the inhibitor's specificity. One reviewer deemed it not informative due to these issues.

Published onApr 12, 2024
Review 4: "Release of P-TEFb from the Super Elongation Complex promotes HIV-1 Latency Reversal"
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Release of P-TEFb from the Super Elongation Complex promotes HIV-1 latency reversal
Release of P-TEFb from the Super Elongation Complex promotes HIV-1 latency reversal

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 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.AUTHOR SUMMARY Since the start of the HIV pandemic, it is estimated that nearly 86 million people have been infected with the virus, and about 40 million people have died. Modern antiretroviral therapies potently restrict viral replication and prevent the onset of AIDS, saving millions of lives. However, these therapies are not curative due to the persistence of the virus in a silenced or ‘latent’ state in long-lived cells of the body. One proposed strategy to clear this latent reservoir, termed “shock and kill”, is to activate these silenced viruses such that the infected cells can be cleared from the body by the immune system. While several drugs have been developed that can activate latent viruses, none have proven effective at reducing the size of the latent reservoir in patients in clinical trials. Here, we describe a new method for latency reactivation using a small molecule inhibitor of a human protein complex called the Super Elongation Complex (SEC). Inhibiting the SEC enhances viral transcription during active infection and triggers the reactivation of latent viruses, especially when in combination with other latency reversing agents. These results pave the way for developing more effective strategies to reactivate latent viruses towards a functional cure.

RR:C19 Evidence Scale rating by reviewer:

  • Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.


Review: In this article, the authors investigate the potential of inhibiting the Super Elongation Complex (SEC) as a strategy to reactivate latent HIV-1 proviruses. It begins with a clear introduction, outlining the critical role of P-TEFb (positive transcription elongation factor b) in regulating transcription elongation. The authors then embark on a series of experiments to explore whether the SEC is indispensable for HIV-1 replication in cell lines and primary CD4+ T cells.

Using multiplexed CRISPR-Cas9 ribonucleoproteins (RNPs), the investigators knocked out various SEC components in cells from multiple healthy donors. Interestingly, while the knockout of P-TEFb components significantly decreased infection rates, the knockout of other SEC components either had no effect or even led to increased infection rates. This suggests that while P-TEFb is essential, other SEC components might be dispensable or could potentially hinder infection. 

To assess the potential therapeutic implications, the study introduces KL-2, a small molecule inhibitor targeting the SEC to release P-TEFb. The findings demonstrate that KL-2 enhances HIV-1 infection in primary CD4+ T cells, especially when combined with other latency reversing agents (LRAs), as indicated by qRT-PCR results showing elevated viral transcription initiation and elongation. However, concerns arise regarding the toxicity observed at higher concentrations of KL-2, prompting further investigation into its safety profile and its non-specific effects.

Furthermore, the study explores the synergistic effects of KL-2 with other LRAs in reactivating latent viral reservoirs, using both J-Lat and other cell line models and PBMCs from aviremic patients. While J-Lat models provide convenient tools for experimentation, questions persist about their physiological relevance compared to primary T cells. The authors additionally evaluate the requirement of Tat in KL-2 induced latency reversal reveals and they found cell line-specific responses. This finding aligns with expected variations in signaling among different cell lines utilized. Nonetheless, experiments with patient-derived PBMCs strengthen the argument for KL-2's potential therapeutic utility.

Despite these promising findings, the study raises several caveats and challenges. The translatability of KL-2 or P-TEFb inhibitors to clinical settings remains uncertain, particularly concerning toxicity. Moreover, the efficacy of Shock and Kill approaches in reducing or eradicating viral reservoirs in vivo has been limited, highlighting the need for more comprehensive strategies that address immunological barriers and non-specific effects of LRAs.
In conclusion, while the study offers valuable insights into the role of SEC inhibition in HIV-1 eradication strategies, further research is warranted to address the identified limitations and advance towards more effective therapeutic interventions.

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