Quantitative polymerase chain reaction; QVOA, quantitative viral outgrowth assays; Rev, regulator of virion expression; RNA, ribonucleic acid; RNAPII, RNA polymerase II; RT-ddPCR, teverse transcription droplet digital PCR; SAHA, suberoylanilide hydroxamic acid; SIV, simian immunodeficiency virus; SMAC, second mitochondrial activator of caspases; SMYD2, SET (Suppressor of variegation, Enhancer of Zeste, Trithorax) and MYND (Myeloid-Nervy-DEAF1) domain-containing protein 2; Sp1, specificity protein 1; STAT5, signal transducer and activator of transcription 5; Suv39H1, Suppressor of variegation 3-9 homolog 1

Human immunodeficiency virus 1 (HIV-1) replicates through the integration of its viral DNA into the genome of human immune target cells. Chronically infected individuals thus carry a genomic burden of virus-derived sequences that persists through antiretroviral therapy. This burden consists of a small fraction of intact, but transcriptionally silenced, i.e. latent, viral genomes and a dominant fraction of defective sequences. Remarkably, all viral-derived sequences are subject to interaction with host cellular physiology at various levels. In this review, we focus on epigenetic aspects of this interaction. We provide a comprehensive overview of how epigenetic mechanisms contribute to establishment and maintenance of HIV-1 gene repression during latency. We furthermore summarize findings indicating that HIV-1 infection leads to changes in the epigenome of target and bystander immune cells. Finally, we discuss how an improved understanding of epigenetic features and mechanisms involved in HIV-1 infection could be exploited for clinical use.

Among many cellular transcriptional regulators, Bcl11b/CTIP2 and HGMA1 have been described to control the establishment and the persistence of HIV-1 latency in microglial cells, the main viral reservoir in the brain. In this present work, we identify and characterize a transcription factor i.e. HIC1, which physically interacts with both Bcl11b/CTIP2 and HMGA1 to co-regulate specific subsets of cellular genes and the viral HIV-1 gene. Our results suggest that HIC1 represses Tat dependent HIV-1 transcription. Interestingly, this repression of Tat function is linked to HIC1 K314 acetylation status and to SIRT1 deacetylase activity. Finally, we show that HIC1 interacts and cooperates with HGMA1 to regulate Tat dependent HIV-1 transcription. Our results also suggest that HIC1 repression of Tat function happens in a TAR dependent manner and that this TAR element may serve as HIC1 reservoir at the viral promoter to facilitate HIC1/TAT interaction.

Eradicating HIV-1 in infected individuals will not be possible without addressing the persistence of the virus in its multiple reservoirs. In this context, the molecular characterization of HIV-1 persistence is key for the development of rationalized therapeutic interventions. HIV-1 gene expression relies on the redundant and cooperative recruitment of cellular epigenetic machineries to cis-regulatory proviral regions. Furthermore, the complex repertoire of HIV-1 repression mechanisms varies depending on the nature of the viral reservoir, although, so far, few studies have addressed the specific regulatory mechanisms of HIV-1 persistence in other reservoirs than the well-studied latently infected CD4+ T cells. Here, we present an exhaustive and updated picture of the heterochromatinization of the HIV-1 promoter in its different reservoirs. We highlight the complexity, heterogeneity and dynamics of the epigenetic mechanisms of HIV-1 persistence, while discussing the importance of further understanding HIV-1 gene regulation for the rational design of novel HIV-1 cure strategies.