Epigenetic control of HIV-1 post integration latency: implications for therapy

Abstract

With the development of effective combined anti-retroviral therapy (cART), there is significant reduction in deaths associated with human immunodeficiency virus type 1 (HIV-1) infection. However, the complete cure of HIV-1 infection is difficult to achieve without the elimination of latent reservoirs which exist in the infected individuals even under cART regimen. These latent reservoirs established during early infection have long life span, include resting CD4+ T cells, macrophages, central nervous system (CNS) resident macrophage/microglia, and gut-associated lymphoid tissue/macrophages, and can actively produce virus upon interruption of the cART. Several epigenetic and non-epigenetic mechanisms have been implicated in the regulation of viral latency. Epigenetic mechanisms such as histone post translational modifications (e.g., acetylation and methylation) and DNA methylation of the proviral DNA and microRNAs are involved in the establishment of HIV-1 latency. The better understanding of epigenetic mechanisms modulating HIV-1 latency could give clues for the complete eradication of these latent reservoirs. Several latency-reversing agents (LRA) have been found effective in reactivating HIV-1 reservoirs in vitro, ex vivo, and in vivo. Some of these agents target epigenetic modifications to elicit viral expression in order to kill latently infected cells through viral cytopathic effect or host immune response. These therapeutic approaches aimed at achieving a sterilizing cure (elimination of HIV-1 from the human body). In the present review, we will discuss our current understanding of HIV-1 epigenomics and how this information can be moved from the laboratory bench to the patient’s bedside.

Epigenetic regulation of hepatitis B virus covalently closed circular DNA: Implications for epigenetic therapy against chronic hepatitis B

“…“Shock and kill” is one of the most discussed and tested therapeutic strategies against HIV‐1, which refers to the induction of latent provirus by various latency‐reversing agents, followed by elimination of the infected cells by the immune system or by cell lysis induced by a viral cytopathic effect and prevention of new infection by combined antiretroviral therapy . DNMT, KMT, and HDAC inhibitors have been used in activating the latent reservoir of HIV‐1 . In terms of HBV, high‐dose IFN‐α treatment has been reported to lead to cccDNA degradation through apolipoprotein B mRNA editing enzyme, catalytic polypeptide‐like 3 (APOBEC3)A‐mediated cytidine deamination of one strand of cccDNA, by which induces mismatch mutations in cccDNA for Apurinic/Apyrimidinic‐endonuclease‐1‐mediated degradation .…”

Epigenome-wide differential DNA methylation between HIV-infected and uninfected individuals

“…Epigenetic mechanisms are involved in human immunodeficiency virus-1 (HIV-1) integration into the host genome 1-3 and viral latency 4-6 . Epigenetic modifications regulate gene transcription and expression without changing the DNA sequence.…”

Limited HIV-1 Reactivation in Resting CD4+ T cells from Aviremic Patients under Protease Inhibitors

“…Indeed, the persistence of latent reservoirs of replication-competent proviruses remains a major obstacle in HIV-1 eradication45. Latent reservoirs are established early during acute viral infection and include among others, macrophages and latently infected resting CD4 + T cells, these later being the main viral reservoir678.…”