Intragenic proviral elements support transcription of defective HIV-1 proviruses.

Autor: Kuniholm J; Boston University School of Medicine, Department of Microbiology, Boston, Massachusetts, United States of America., Armstrong E; Boston University School of Medicine, Department of Medicine, Section of Infectious Diseases; Boston, Massachusetts, United States of America., Bernabe B; Boston University School of Medicine Graduate Medical Sciences, Boston, Massachusetts, United States of America., Coote C; Boston University School of Medicine, Department of Medicine, Section of Infectious Diseases; Boston, Massachusetts, United States of America., Berenson A; Boston University, Department of Biology, Boston, Massachusetts, United States of America., Patalano SD; Boston University, Department of Biology, Boston, Massachusetts, United States of America., Olson A; Boston University School of Medicine, Department of Medicine, Section of Infectious Diseases; Boston, Massachusetts, United States of America., He X; Boston University School of Medicine, Department of Medicine, Section of Infectious Diseases; Boston, Massachusetts, United States of America., Lin NH; Boston University School of Medicine, Department of Medicine, Section of Infectious Diseases; Boston, Massachusetts, United States of America., Fuxman Bass JI; Boston University, Department of Biology, Boston, Massachusetts, United States of America., Henderson AJ; Boston University School of Medicine, Department of Microbiology, Boston, Massachusetts, United States of America.; Boston University School of Medicine, Department of Medicine, Section of Infectious Diseases; Boston, Massachusetts, United States of America.; Boston University School of Medicine Graduate Medical Sciences, Boston, Massachusetts, United States of America.
Jazyk: angličtina
Zdroj: PLoS pathogens [PLoS Pathog] 2021 Dec 28; Vol. 17 (12), pp. e1009982. Date of Electronic Publication: 2021 Dec 28 (Print Publication: 2021).
DOI: 10.1371/journal.ppat.1009982
Abstrakt: HIV-1 establishes a persistent proviral reservoir by integrating into the genome of infected host cells. Current antiretroviral treatments do not target this persistent population of proviruses which include latently infected cells that upon treatment interruption can be reactivated to contribute to HIV-1 rebound. Deep sequencing of persistent HIV proviruses has revealed that greater than 90% of integrated HIV genomes are defective and unable to produce infectious virions. We hypothesized that intragenic elements in the HIV genome support transcription of aberrant HIV-1 RNAs from defective proviruses that lack long terminal repeats (LTRs). Using an intact provirus detection assay, we observed that resting CD4+ T cells and monocyte-derived macrophages (MDMs) are biased towards generating defective HIV-1 proviruses. Multiplex reverse transcription droplet digital PCR identified env and nef transcripts which lacked 5' untranslated regions (UTR) in acutely infected CD4+ T cells and MDMs indicating transcripts are generated that do not utilize the promoter within the LTR. 5'UTR-deficient env transcripts were also identified in a cohort of people living with HIV (PLWH) on ART, suggesting that these aberrant RNAs are produced in vivo. Using 5' rapid amplification of cDNA ends (RACE), we mapped the start site of these transcripts within the Env gene. This region bound several cellular transcription factors and functioned as a transcriptional regulatory element that could support transcription and translation of downstream HIV-1 RNAs. These studies provide mechanistic insights into how defective HIV-1 proviruses are persistently expressed to potentially drive inflammation in PLWH.
Competing Interests: The authors have declared that no competing interests exist
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje