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.

Keywords: CD4+ T cells; Epigenetics; HIV-1; Histone modifications; Latency; MicroRNAs; Microglia; Monocyte/macrophage.

Fig. 1

Targeting latent HIV-1 reservoirs. HIV-1 primarily infects CD4⁺ T cells and cells of monocyte/macrophage lineage. Viral latency has been extensively studied in CD4⁺ T cells and to some extent in monocytes/macrophages, microglia , and gut-associated lymphoid tissue macrophages. These latent reservoirs represent the key issue pertaining to the complete eradication of HIV-1 from the infected individuals. According to “kick and kill” strategy, virus can be activated in these reservoirs using a range of latency reversing agents which include HDACis, HMTis, DNMTis, PKC agonists, and several other small molecules. Impact of these LRAs has been well studied in CD4⁺ T cells and to lesser extent in the cells of monocyte/macrophage lineage. Upon reactivation, latent virus undergoes robust replication resulting in production of enormous amount of virus which can induce the lysis of target cells or infected cells can be recognized by the cellular immune clearance machinery. In addition, fresh infection should be stopped by cART. The impact of LRAs in reactivating latent virus in the cells of monocyte/macrophage lineage is not well studied and needs further investigations