While social media mavens may consider “going viral” the zenith of their existence, latent virus reactivation represents a significant cause of morbidity and mortality in transplant patients. Now, in an extremely “likable” study, a tweetable team of researchers has described how epigenetic inhibitors may be an efficient means of selectively purging viral reservoirs before transplantation and improving outcomes.
Specifically, the avid Facebookers and TikTokers from the lab of Ian Groves and Mark Wills (University of Cambridge, UK) sought to identify epigenetic inhibitors that induce human cytomegalovirus (HCMV) lytic gene expression (encoding immunogenic antigens) but repress immune evasion gene expression to enhance targeting of latently-infected cells by the host immune system. Overall, they hope that this “pre-emptive epigenetic strike” may significantly reduce transplant-associated morbidity and mortality.
So, let’s set aside those latte art pictures and cat videos and read the top comments on this shareable study from Groves and colleagues:
- Initial screens using monocytes and fibroblasts identified inhibitors of histone deacetylases and bromodomain-containing proteins (the “readers” of lysine acetylation) as inducers of virus immediate-early gene expression
- However, an ex vivo monocyte model of experimental HCMV latency revealed that histone deacetylase inhibitor exposure produces infectious virions
- Alternatively, inhibitors specific to bromodomain and extraterminal (BET) proteins (BRD2, 3, and 4 and BRDT) restrict full viral reactivation
- At the molecular level, transcriptionally repressive complexes sequestered the P-TEFb transcriptional activator complex through an interaction with BRD4 to promote HCMV latency
- BET inhibitor treatment releases P-TEFb to prompt the transcription of lytic genes (such as IE72, pp65, and gB) from latently-infected cells without inducing immune evasion gene expression
- Moreover, inhibitor treatment also restricts viral DNA replication and full reactivation
- Finally, the authors demonstrated how BET inhibitor-mediated transcriptional dysregulation of virally-associated genes allows for specific immune targeting and cytotoxic T cell-mediated killing of experimentally- and naturally-infected HCMV latent cells
- Importantly, BET inhibitor treatment reduces the presence of HCMV viral DNA in ex-vivo–treated peripheral blood cells isolated from HCMV-seropositive individuals
This article is more than just social media “clickbait” – the “influencers” behind this fascinating study underscore the enormous potential for BET inhibitor pretreatment to reduce transplant-associated morbidity and mortality and aim for further investigations in patient populations as the crucial next step.
Lead author Ian Groves shares, “This would be the first type of treatment to reduce HCMV infection levels pre-transplant in order to lower the chances of virus reactivation during immune suppression after transplantation. Our findings could lead to thousands of lives being saved every year. In addition to the terrible human suffering this virus causes, treating its effects adds enormously to the high costs already incurred by transplantation. It’s a really serious issue for health services in wealthy nations and a desperate one in developing countries. Our findings offer an opportunity to transform this horrible situation.”
For more on how a pre-emptive strike with epigenetic inhibitors may stop transplants going viral and improve patient outcomes, see PNAS, March 2021.