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Deciphering the Epigenetic Regulation of HIV-1 Latency using CUT&RUN

By Stuart P. Atkinson, Ph.D.

September 12, 2024

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Introduction: The Problem of HIV-1 Latency – Is Epigenetic Regulation A Factor?

A long-lived "latent" population of HIV-1-infected CD4 T cells persists after anti-retroviral therapy and prevents lasting positive therapeutic outcomes in affected patients. Viral latency involves the silencing of viral gene expression within long-lived memory CD4 T cells, which makes the virus invisible to the immune system and supports persistence and reactivation (and clonal expansion of infected cells) if treatment is discontinued (Chun et al.).

The exogenously induced reactivation of viral gene expression may render HIV-1-infected CD4 T cells vulnerable to clearance by viral cytopathic effects or immune mechanisms; however, current so-called latency-reversing approaches targeting host-cell mechanisms remain inefficient (Ho et al. and Einkauf et al.), which may derive from the presence of multiple layers of transcriptional and epigenetic repression that act on the virus (Pearson et al. and Rafati et al.).

In a previous study, researchers headed by Edward P. Browne (University of North Carolina) reported the reversible nature of the HIV-1 viral gene silencing in CD4 T cells that promotes viral latency (Jefferys et al.). In their new study, which involved the cleavage under target and release under nuclease (CUT&RUN) chromatin profiling technique to evaluate the distribution of histone modifications in low-cell number samples, the team enquired whether targeting epigenetic enzymes that promote initial viral silencing could prevent latency from occurring rather than attempting the more "epigenetically challenging" task of reactivating already silenced viral gene expression.

Such an approach would require more in-depth knowledge regarding the epigenetic layers regulating entry into viral latency; could CUT&RUN help to decipher the epigenetic regulation of HIV-1 latency? The lab's exciting new study, reported recently in Cell Chemical Biology, now highlights a critical role for histone deacetylases (HDACs) and epigenetic reprogramming in establishing HIV-1 latency and suggests that HDAC targeting in combination with anti-retroviral therapy may represent a viable therapeutic strategy. Overall, these findings could prompt the development of a safe and efficient combination therapy that rids the body of HIV-1 infection for good (Peterson et al.).

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Deciphering the Epigenetics of HIV-1 Latency: CUT&RUN Lends a Hand

Peterson et al. employed various targeted HDAC inhibitors, an HDAC3-directed proteolysis targeting chimera (PROTAC) (Xiao et al.), and CRISPR-mediated HDAC knockouts in an HIV-1-infected CD4 T cell model system (Jefferys et al. and Bradley et al.) to reveal how HDAC1/2 or HDAC3 inhibition sufficed to prevent HIV-1 latency (by maintaining viral gene expression). However, combined HDAC1/2 and HDAC3 inhibition would be required to reverse HIV-1 latency (by reactivating viral gene expression) thanks to the supposed presence of additional epigenetic layers of regulation.

Interestingly, blocking HDAC activity in HIV-1-infected CD4 T cells effectively prevented proviruses from entering latency even after HDAC inhibitor removal, suggesting that the induced epigenetic modifications reprogram the provirus or CD4 T cells to prevent viral latency. In detail, the authors report the differing contribution of individual class I HDACs to HIV-1 silencing in CD4 T cells - HDAC1/2 and HDAC3 play essential but mechanistically distinct roles in initiating viral latency in CD4 T cells, while HDAC2 compensates for the loss of HDAC1.

The authors also applied CUT&RUN (Skene et al. and Meers et al.) to reveal that modulating HDAC activity prompted significant epigenetic reprogramming. The implementation of this cutting-edge technique revealed increased H3K9ac deposition and decreased H3K9me3 deposition at the viral promoter (the long terminal repeat) associated with the HDAC inhibition-mediated prevention of HIV-1 latency, overall suggesting that an H3K9ac/H3K9me3 "epigenetic switch" constitutes a critical viral regulatory mechanism.

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The Future of HDAC Inhibitors in Preventing HIV-1 Latency

Overall, deciphering the epigenetic regulation of HIV-1 latency suggests that drugs that target epigenetic modifiers combined with anti-retroviral therapy may support the complete clearance of HIV-1 from an affected patient. Specifically, these data support a role for HDACs in viral latency, highlight the importance of an H3K9ac/H3K9me3 switch in controlling viral gene expression (thanks to CUT&RUN), and suggest distinct and non-redundant roles for HDAC1/2 and HDAC3.

For more on how an epigenetic exploration defined the mechanisms controlling HIV-1 latency with the help of CUT&RUN, see Cell Chemical Biology, December 2023.

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About the author

Stuart P. Atkinson, Ph.D.

Stuart was born and grew up in the idyllic town of Lanark (Scotland). He later studied biochemistry at the University of Strathclyde in Glasgow (Scotland) before gaining his Ph.D. in medical oncology; his thesis described the epigenetic regulation of the telomerase gene promoters in cancer cells. Following Post-doctoral stays in Newcastle (England) and Valencia (Spain) where his varied research aims included the exploration of epigenetics in embryonic and induced pluripotent stem cells, Stuart moved into project management and scientific writing/editing where his current interests include polymer chemistry, cancer research, regenerative medicine, and epigenetics. While not glued to his laptop, Stuart enjoys exploring the Spanish mountains and coastlines (and everywhere in between) and the food and drink that it provides!

Contact Stuart on Twitter with any questions

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