HIV latency reversing agents act through Tat post translational modifications

Retrovirology
Georges KhouryDamian F J Purcell

Abstract

Different classes of latency reversing agents (LRAs) are being evaluated to measure their effects in reactivating HIV replication from latently infected cells. A limited number of studies have demonstrated additive effects of LRAs with the viral protein Tat in initiating transcription, but less is known about how LRAs interact with Tat, particularly through basic residues that may be post-translationally modified to alter the behaviour of Tat for processive transcription and co-transcriptional RNA processing. Here we show that various lysine and arginine mutations reduce the capacity of Tat to induce both transcription and mRNA splicing. The lysine 28 and lysine 50 residues of Tat, or the acetylation and methylation modifications of these basic amino acids, were essential for Tat transcriptional control, and also for the proviral expression effects elicited by histone deacetylase inhibitors (HDACi) or the bromodomain inhibitor JQ1. We also found that JQ1 was the only LRA tested that could induce HIV mRNA splicing in the absence of Tat, or rescue splicing for Tat lysine mutants in a BRD4-dependent manner. Our data provide evidence that Tat activities in both co-transcriptional RNA processing together with transcriptional initiat...Continue Reading

References

Jun 25, 1996·Proceedings of the National Academy of Sciences of the United States of America·S EmilianiE Verdin
Nov 2, 1999·The EMBO Journal·R E KiernanC Van Lint
Jun 1, 2001·The Journal of Biological Chemistry·E ColS Khochbin
Jul 31, 2003·Molecular Cell·Katrin KaehlckeMelanie Ott
Nov 6, 2004·The Journal of Infectious Diseases·Marek FischerUNKNOWN Swiss HIV Cohort Study
May 20, 2005·Current Opinion in Cell Biology·David L Bentley
May 20, 2005·Current Opinion in Cell Biology·Alberto R Kornblihtt
Jul 15, 2006·PLoS Pathogens·Kara G LassenRobert F Siliciano
Mar 8, 2007·Nucleic Acids Research·Matjaz BarboricQiang Zhou
Aug 11, 2007·Proceedings of the National Academy of Sciences of the United States of America·Dwayne A BisgroveEric Verdin
May 24, 2008·Retrovirology·Rachel Van DuyneFatah Kashanchi
Jan 13, 2009·The Journal of Biological Chemistry·Xavier ContrerasB Matija Peterlin
Sep 4, 2009·Journal of Virology·Haran SivakumaranDavid Harrich
Dec 8, 2009·Nucleic Acids Research·Joseph A JablonskiMassimo Caputi
Sep 28, 2010·Nature·Panagis FilippakopoulosJames E Bradner
Nov 22, 2011·Cell Host & Microbe·Melanie OttQiang Zhou
Dec 30, 2011·Journal of Virology·Karen ChiangAndrew P Rice
Feb 23, 2012·Cold Spring Harbor Perspectives in Medicine·Jonathan Karn, C Martin Stoltzfus
Jul 18, 2012·Journal of Leukocyte Biology·Camellia BanerjeeMonty Montano
Oct 9, 2012·Cell Reports·Jian ZhuAbraham L Brass

❮ Previous
Next ❯

Citations

Jul 18, 2019·Clinical & Translational Immunology·Steven M Heaton
Apr 25, 2020·Viruses·Nabab KhanJonathan D Geiger
Jun 17, 2020·Journal of Immunology Research·Hager MohamedFred C Krebs
Feb 5, 2021·European Journal of Medicinal Chemistry·Juliana Romano LopesJean Leandro Dos Santos
Jul 10, 2021·Biochimie·Amjad AliAkhil Chandra Banerjea
Aug 21, 2020·Current HIV Research·Edward K MainaRaphael M Lwembe

❮ Previous
Next ❯

Methods Mentioned

BETA
acetylation
flow cytometry
transfection
PCR
flow cytometry gating
histone acetylation
ISS
Assay

Software Mentioned

QuantaSoft
GraphPad PRISM

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.