IL-15 regulates susceptibility of CD4+T cells to HIV infection DOI Open Access
Lara Manganaro, Patrick Hong, Matthew M. Hernandez

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2018, Volume and Issue: 115(41)

Published: Sept. 26, 2018

HIV integrates into the host genome to create a persistent viral reservoir. Stimulation of CD4+ memory T lymphocytes with common γc-chain cytokines renders these cells more susceptible infection, making them key component reservoir itself. IL-15 is up-regulated during primary time when established. Therefore, we investigated molecular and cellular impact on T-cell infection. We found that stimulation induces SAM domain HD domain-containing protein 1 (SAMHD1) phosphorylation due cell cycle entry, relieving an early block Perturbation pathways downstream receptor (IL-15R) indicated SAMHD1 after JAK dependent. Treating Ruxolitinib, inhibitor JAK1 JAK2, effectively blocked IL-15-induced protected from Using high-resolution single-cell immune profiling using mass cytometry by TOF (CyTOF), altered composition populations increasing proliferation cells, including stem (TSCM). IL-15-stimulated TSCM, harboring phosphorylated SAMHD1, were preferentially infected. propose plays pivotal role in creating self-renewing, facilitating infection cell-like properties. Time-limited interventions inhibitors, such as should prevent inactivation endogenous restriction factor protect this long-lived T-memory population

Language: Английский

NONO Detects the Nuclear HIV Capsid to Promote cGAS-Mediated Innate Immune Activation DOI Creative Commons
Xavier Lahaye, Matteo Gentili,

Aymeric Silvin

et al.

Cell, Journal Year: 2018, Volume and Issue: 175(2), P. 488 - 501.e22

Published: Sept. 27, 2018

Language: Английский

Citations

193
Application of CRISPR/Cas9-Based Gene Editing in HIV-1/AIDS Therapy DOI Creative Commons
Qiaoqiao Xiao, Deyin Guo, Shuliang Chen

et al.

Frontiers in Cellular and Infection Microbiology, Journal Year: 2019, Volume and Issue: 9

Published: March 22, 2019

Despite the fact that great efforts have been made in prevention and resistance of HIV-1 infection, HIV-1/AIDS remains a major threat to global human health. Highly active antiretroviral therapy (HAART) can suppress virus replication, but it cannot eradicate latent viral reservoirs patients. Recently, clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated nuclease 9 (Cas9) system has engineered as an effective gene-editing technology with potential treat HIV-1/AIDS. It be used target cellular co-factors or genome reduce infection clear provirus, well induce transcriptional activation for elimination. This versatile gene editing successfully applied reduction cells animal models. Here, we update rapid progress CRISPR/Cas9-based research recent years discuss limitations future perspectives its application.

Language: Английский

Citations

151
Genome surveillance by HUSH-mediated silencing of intronless mobile elements DOI Creative Commons
Marta Seczyńska,

Stuart Bloor,

Sergio Martínez Cuesta

et al.

Nature, Journal Year: 2021, Volume and Issue: 601(7893), P. 440 - 445

Published: Nov. 18, 2021

Abstract All life forms defend their genome against DNA invasion. Eukaryotic cells recognize incoming and limit its transcription through repressive chromatin modifications. The human silencing hub (HUSH) complex transcriptionally represses long interspersed element-1 retrotransposons (L1s) retroviruses histone H3 lysine 9 trimethylation (H3K9me3) 1–3 . How HUSH recognizes initiates of these invading genetic elements is unknown. Here we show that able to repress a broad range long, intronless transgenes. Intron insertion into HUSH-repressed transgenes counteracts repression, even in the absence intron splicing. binds transcripts from target locus, prior independent H3K9me3 deposition, essential for both initiation propagation HUSH-mediated H3K9me3. Genomic data reveal how subset endogenous genes generated retrotransposition cellular mRNAs. Thus cDNA—the hallmark reverse transcription—provides versatile way distinguish retroelements host enables protect ‘non-self’ DNA, despite there being no previous exposure element. Our findings existence transcription-dependent genome-surveillance system explain it provides immediate protection newly acquired while avoiding inappropriate repression genes.

Language: Английский

Citations

109
Transposon–host arms race: a saga of genome evolution DOI
Yuka W. Iwasaki, Keisuke Shoji,

Shinichi Nakagwa

et al.

Trends in Genetics, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

Citations

2
A virus-packageable CRISPR screen identifies host factors mediating interferon inhibition of HIV DOI Creative Commons
Molly OhAinle, Louisa Helms,

Jolien Vermeíre

et al.

eLife, Journal Year: 2018, Volume and Issue: 7

Published: Dec. 6, 2018

Interferon (IFN) inhibits HIV replication by inducing antiviral effectors. To comprehensively identify IFN-induced restriction factors, we assembled a CRISPR sgRNA library of Stimulated Genes (ISGs) into modified lentiviral vector that allows for packaging sgRNA-encoding genomes in trans budding HIV-1 particles. We observed knockout Zinc Antiviral Protein (ZAP) improved the performance screen due to ZAP-mediated inhibition vector. A small panel including MxB, IFITM1, Tetherin/BST2 and TRIM5alpha together explain inhibitory effects IFN on CXCR4-tropic strain, HIV-1LAI, THP-1 cells. second with CCR5-tropic primary HIV-1Q23.BG505, described an overlapping, but non-identical, factors. Further, this also identifies dependency The ability factors inhibit strains replicate human cells suggests these are incompletely antagonized.This article has been through editorial process which authors decide how respond issues raised during peer review. Reviewing Editor's assessment is all have addressed (see decision letter).

Language: Английский

Citations

139
NP220 mediates silencing of unintegrated retroviral DNA DOI
Yiping Zhu,

Gary Z. Wang,

Oya Cingöz

et al.

Nature, Journal Year: 2018, Volume and Issue: 564(7735), P. 278 - 282

Published: Nov. 27, 2018

Language: Английский

Citations

113
The HUSH complex is a gatekeeper of type I interferon through epigenetic regulation of LINE-1s DOI Creative Commons
Hale Tunbak, Rocio Enriquez-Gasca, Christopher H.C. Tie

et al.

Nature Communications, Journal Year: 2020, Volume and Issue: 11(1)

Published: Nov. 3, 2020

Abstract The Human Silencing Hub (HUSH) complex is necessary for epigenetic repression of LINE-1 elements. We show that HUSH-depletion in human cell lines and primary fibroblasts leads to induction interferon-stimulated genes (ISGs) through JAK/STAT signaling. This effect mainly attributed MDA5 RIG-I sensing double-stranded RNAs (dsRNAs). coincides with upregulation primate-conserved LINE-1s, as well increased expression full-length hominid-specific LINE-1s produce bidirectional RNAs, which may form dsRNA. Notably, LTRs nearby ISGs are derepressed likely rendering these more responsive interferon. shRNAs can abrogate the HUSH-dependent response, while overexpression an engineered construct activates interferon Finally, we HUSH component, MPP8 frequently downregulated diverse cancers its depletion DNA damage. These results suggest drive physiological or autoinflammatory responses dsRNA gene-regulatory roles controlled by complex.

Language: Английский

Citations

111
Key Viral Adaptations Preceding the AIDS Pandemic DOI Creative Commons
Daniel Sauter, Frank Kirchhoff

Cell Host & Microbe, Journal Year: 2019, Volume and Issue: 25(1), P. 27 - 38

Published: Jan. 1, 2019

Language: Английский

Citations

95
Promiscuous Targeting of Cellular Proteins by Vpr Drives Systems-Level Proteomic Remodeling in HIV-1 Infection DOI Creative Commons
Edward JD Greenwood, James C. Williamson,

Agata Sienkiewicz

et al.

Cell Reports, Journal Year: 2019, Volume and Issue: 27(5), P. 1579 - 1596.e7

Published: April 1, 2019

Language: Английский

Citations

92
TASOR is a pseudo-PARP that directs HUSH complex assembly and epigenetic transposon control DOI Creative Commons
Christopher H. Douse, Iva A. Tchasovnikarova, Richard T. Timms

et al.

Nature Communications, Journal Year: 2020, Volume and Issue: 11(1)

Published: Oct. 2, 2020

Abstract The HUSH complex represses retroviruses, transposons and genes to maintain the integrity of vertebrate genomes. regulates deposition epigenetic mark H3K9me3, but how its three core subunits — TASOR, MPP8 Periphilin contribute assembly targeting remains unknown. Here, we define biochemical basis find that modular architecture resembles yeast RNA-induced transcriptional silencing complex. central subunit, associates with RNA processing components. TASOR is required for H3K9me3 over LINE-1 repeats repetitive exons in transcribed genes. In context previous studies, this suggests an intermediate important activity. We dissect domains necessary transgene repression. Structure-function analyses reveal bears a catalytically-inactive PARP domain targeted deposition. conclude multifunctional pseudo-PARP directs regulation genomic targets.

Language: Английский

Citations

74