Chromatin maturation of the HIV-1 provirus in primary resting CD4+ T cells


Autoři: Birgitta Lindqvist aff001;  Sara Svensson Akusjärvi aff002;  Anders Sönnerborg aff002;  Marios Dimitriou aff004;  J. Peter Svensson aff001
Působiště autorů: Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden aff001;  Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden aff002;  Department of Medicine Huddinge, Division of Infectious Diseases, Karolinska Institutet, Huddinge, Sweden aff003;  Department of Medicine Huddinge, Center for Hematology and Regenerative Medicine, Karolinska Institutet, Huddinge, Sweden aff004
Vyšlo v časopise: Chromatin maturation of the HIV-1 provirus in primary resting CD4+ T cells. PLoS Pathog 16(1): e1008264. doi:10.1371/journal.ppat.1008264
Kategorie: Research Article
doi: 10.1371/journal.ppat.1008264

Souhrn

Human immunodeficiency virus type 1 (HIV-1) infection is a chronic condition, where viral DNA integrates into the genome. Latently infected cells form a persistent, heterogeneous reservoir that at any time can reactivate the integrated HIV-1. Here we confirmed that latently infected cells from HIV-1 positive study participants exhibited active HIV-1 transcription but without production of mature spliced mRNAs. To elucidate the mechanisms behind this we employed primary HIV-1 latency models to study latency establishment and maintenance. We characterized proviral transcription and chromatin development in cultures of resting primary CD4+ T-cells for four months after ex vivo HIV-1 infection. As heterochromatin (marked with H3K9me3 or H3K27me3) gradually stabilized, the provirus became less accessible with reduced activation potential. In a subset of infected cells, active marks (e.g. H3K27ac) and elongating RNAPII remained detectable at the latent provirus, despite prolonged proviral silencing. In many aspects, latent HIV-1 resembled an active enhancer in a subset of resting cells. The enhancer chromatin actively promoted latency and the enhancer-specific CBP/P300-inhibitor GNE049 was identified as a new latency reversal agent. The division of the latent reservoir according to distinct chromatin compositions with different reactivation potential enforces the notion that even though a relatively large set of cells contains the HIV-1 provirus, only a discrete subset is readily able to reactivate the provirus and spread the infection.

Klíčová slova:

Flow cytometry – Heterochromatin – HIV – HIV-1 – Chromatin – Primary cells – T cells – Viral persistence and latency


Zdroje

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