Recent research underscored that HIV transcription remains a critical step in the viral life cycle. Especially the transition between active and latent infection is critically regulated by viral factors such as Tat and many host factors that either control the transcriptional activity of the virus directly or the epigenetic landscape around it. It has become apparent that during antiretroviral therapy 81% of the viral reservoir remains transcriptionally active while “true” latency mainly exists in viruses embedded in a very repressive chromatin environment especially near repetitive genomic elements. Reactivation of HIV transcription from latency involves a shift to a permissive chromatin state, driven by histone acetylation, recruitment of bromodomain-containing proteins, and the viral protein Tat, which recruits the positive transcription elongation factor b to release RNA polymerase II from pausing. Therapeutically, modalities targeting epigenetic proteins such as histone deacetylases, bromodomains, or histone methyltransferases as well as Tat are being studied to either reactivate latent proviruses for eradication or reinforce latency to suppress reactivation. Successfully suppressing transcriptional activity in the reservoir during antiretroviral therapy is promising as it decreases the chances of viral reactivation and is critical to alleviate chronic immune activation, which otherwise fuels early appearance of chronic diseases of aging. We speculate that suppressing transcription will also change the epigenetic landscape of the integrated proviruses in a durable way to long-term tune down reactivation potential. We will discuss the mechanisms of HIV transcription in the context of chromatin and our ongoing efforts to inhibit the transcriptionally active reservoir.
CROI Conference
