HIV-1 accessory protein Vpr possesses a cryptic p300-dependent transcription-promoting activity that is blocked by histone deacetylases in CD4+T cells DOI Creative Commons
Catherine A. Lewis, David M. Margolis, Edward P. Browne

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 27, 2025

Abstract Antiretroviral therapy (ART) has dramatically improved the clinical prognosis for people with HIV and prevents transmission. However, ART does not cure infection because of a persistent, latent reservoir in long-lived cells such as central memory CD4 + T (T CM ) cells. Eliminating or preventing formation will require better understanding HIV-1 latency establishment. We others have recently shown that host cell factors histone deacetylases (HDACs) are critical cellular allow entry into latency. Whether HDACs interact specific viral to regulate establishment, however, is unknown. To examine role individual accessory proteins, we constructed panel reporter strains, each expressing single protein, examined them primary T-cell model. Interestingly, found HDAC inhibitor (HDACi) vorinostat potently enhances effect protein Vpr promoting expression infected cells, suggesting possesses cryptic transcription-promoting activity restricted by HDACs. This was dependent on p300-binding domain inhibited selective p300 acetyltransferase inhibitor. also resulted significant increase proportion phenotype. Furthermore, observed were more resistant Vpr-induced apoptosis/cell death than other subtypes, indicating during selects proviruses Overall, these findings suggest plays an important shaping results, part, from HDAC-mediated restriction Vpr’s activity. Understanding how shape establishment aid development new latency-targeting therapies. Author Summary Although antiretroviral effective at treating HIV, remains elusive. The obstacle presence latently which virus persists despite therapy. Recent work sizable fraction this forms near time initiated, it may be possible prevent some forming. prevention enters latency, including gene silenced. therefore sought interaction between proteins turning off that, whereas turns expression, block Second, leads relative type harbors virus. Our silencing persistence certain types developing approaches targeting

Language: Английский

HIV reprograms host m6Am RNA methylome by viral Vpr protein-mediated degradation of PCIF1 DOI Creative Commons
Qiong Zhang, Yuqi Kang, Shaobo Wang

et al.

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: Sept. 20, 2021

Abstract N 6 ,2′- O -dimethyladenosine (m Am) is an abundant RNA modification located adjacent to the 5′-end of mRNA 7-methylguanosine 7 G) cap structure. m A methylation on 2′- -methylated at 5′-ends mRNAs catalyzed by methyltransferase Phosphorylated CTD Interacting Factor 1 (PCIF1). The role Am and function PCIF1 in regulating host–pathogens interactions are unknown. Here, we investigate dynamics reprogramming host methylome during HIV infection. We show that infection induces a dramatic decrease cellular mRNAs. By using depleted T cells, identify 2237 genes 854 affected Strikingly, find restricts replication. Further mechanism studies viral protein R (Vpr) interacts with ubiquitination degradation. Among genes, inhibits enhancing transcription factor ETS1 (ETS Proto-Oncogene 1, factor) stability binds promoter regulate transcription. Altogether, our study discovers HIV–host interactions, identifies modified cells which infection, reveals how regulates epitranscriptomics through

Language: Английский

Citations

46
HIV-1 Vpr Functions in Primary CD4+ T Cells DOI Creative Commons

Carlos Alberto Vanegas-Torres,

Michael Schindler

Viruses, Journal Year: 2024, Volume and Issue: 16(3), P. 420 - 420

Published: March 9, 2024

HIV-1 encodes four accesory proteins in addition to its structural and regulatory genes. Uniquely amongst them, Vpr is abundantly present within virions, meaning it poised exert various biological effects on the host cell upon delivery. In this way, contributes towards establishment of a successful infection, as evidenced by extent which depends factor achieve full pathogenicity vivo. Although HIV infects types organism, CD4+ T cells are preferentially targeted since they highly permissive productive concomitantly bringing about hallmark immune dysfunction that accompanies spread. The last several decades have seen unprecedented progress unraveling activities possesses at molecular scale, increasingly underscoring importance viral component. Nevertheless, remains controversial whether some these advances bear vivo relevance, commonly employed cellular models significantly differ from primary lymphocytes. One prominent example “established” ability induce G2 cycle arrest, with enigmatic physiological relevance infected objective review discoveries their context illustrate mechanisms whereby supports infection cells, whilst identifying findings require validation physiologically relevant models.

Language: Английский

Citations

6
HIV-1 Vpr antagonizes innate immune activation by targeting karyopherin-mediated NF-κB/IRF3 nuclear transport DOI Creative Commons
Hataf Khan, Rebecca P. Sumner,

Jane Rasaiyaah

et al.

eLife, Journal Year: 2020, Volume and Issue: 9

Published: Dec. 10, 2020

HIV-1 must replicate in cells that are equipped to defend themselves from infection through intracellular innate immune systems. evades sensing encapsidated DNA synthesis and encodes accessory genes antagonize specific antiviral effectors. Here, we show both particle associated, expressed Vpr, the stimulatory effect of a variety pathogen associated molecular patterns by inhibiting IRF3 NF-κB nuclear transport. Phosphorylation at S396, but not S386, was also inhibited. We propose that, rather than promoting import, Vpr interacts with karyopherins disturb their import promote replication macrophages. Concordantly, demonstrate Vpr-dependent rescue human macrophages inhibition cGAMP, product activated cGAS. model unifies manipulation activation transmission.

Language: Английский

Citations

46
Functional proteomic atlas of HIV infection in primary human CD4+ T cells DOI Creative Commons
Adi Naamati, James C. Williamson, Edward JD Greenwood

et al.

eLife, Journal Year: 2019, Volume and Issue: 8

Published: March 11, 2019

Viruses manipulate host cells to enhance their replication, and the identification of cellular factors targeted by viruses has led key insights into both viral pathogenesis cell biology. In this study, we develop an HIV reporter virus (HIV-AFMACS) displaying a streptavidin-binding affinity tag at surface infected cells, allowing facile one-step selection with streptavidin-conjugated magnetic beads. We use system obtain pure populations HIV-infected primary human CD4+ T for detailed proteomic analysis, quantitate approximately 9000 proteins across multiple donors on dynamic background activation. Amongst 650 HIV-dependent changes (q < 0.05), describe novel Vif-dependent targets FMR1 DPH7, 192 not identified and/or regulated in lines, such as ARID5A PTPN22. therefore provide high-coverage functional atlas infection, mechanistic account subverted its natural target cell.

Language: Английский

Citations

44
Vpr and Its Cellular Interaction Partners: R We There Yet? DOI Creative Commons
Helena Fábryová, Klaus Strebel

Cells, Journal Year: 2019, Volume and Issue: 8(11), P. 1310 - 1310

Published: Oct. 24, 2019

Vpr is a lentiviral accessory protein that expressed late during the infection cycle and packaged in significant quantities into virus particles through specific interaction with P6 domain of viral Gag precursor. Characterization physiologically relevant function(s) has been hampered by fact many cell lines, deletion does not significantly affect fitness. However, critical for replication primary macrophages pathogenesis vivo. It generally accepted have enzymatic activity but functions as molecular adapter to modulate or cellular processes benefit virus. Indeed, interacting factors described now, goal this review summarize our current knowledge proteins targeted Vpr.

Language: Английский

Citations

43
Vpr counteracts the restriction of LAPTM5 to promote HIV-1 infection in macrophages DOI Creative Commons
Li Zhao, Shumei Wang, Meng Xu

et al.

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: June 17, 2021

The HIV-1 accessory proteins Vif, Vpu, and Nef can promote infection by overcoming the inhibitory effects of host cell restriction factors APOBEC3G, Tetherin, SERINC5, respectively. However, how protein Vpr enhances in macrophages but not CD4+ T cells remains elusive. Here, we report that counteracts lysosomal-associated transmembrane 5 (LAPTM5), a potent inhibitor particle infectivity, to enhance macrophages. LAPTM5 transports envelope glycoproteins lysosomes for degradation, thereby inhibiting virion infectivity. restrictive triggering its degradation via DCAF1. In absence Vpr, silencing precisely phenocopied effect on infection. contrast, did LAPTM5. Moreover, was highly expressed lymphocytes. Re-expressing reconstituted Vpr-dependent promotion primary cells, as observed Herein, demonstrate molecular mechanism used overcome macrophages, providing potential strategy anti-HIV/AIDS therapeutics.

Language: Английский

Citations

33
Targeting the DNA damage response and repair in cancer through nucleotide metabolism DOI Creative Commons
Thomas Helleday, Sean G. Rudd

Molecular Oncology, Journal Year: 2022, Volume and Issue: 16(21), P. 3792 - 3810

Published: May 18, 2022

The exploitation of the DNA damage response and repair proficiency cancer cells is an important anticancer strategy. replication are dependent upon supply deoxynucleoside triphosphate (dNTP) building blocks, which produced maintained by nucleotide metabolic pathways. Enzymes within these pathways can be promising targets to selectively induce toxic lesions in cells. These same also activate antimetabolites, group chemotherapies that disrupt both metabolism Thus, dNTP enzymes targeted refine use chemotherapeutics, many remain standard care common cancers. In this review article, we will discuss approaches exemplified MTH1, MTHFD2 SAMHD1. © 2022 Authors. Molecular Oncology published John Wiley & Sons Ltd on behalf Federation European Biochemical Societies.

Language: Английский

Citations

27
Enhanced infection efficiency and cytotoxicity mediated by vpx-containing lentivirus in chimeric antigen receptor macrophage (CAR-M) DOI Creative Commons
Yun Gao,

Yue Ju,

Xiaomeng Ren

et al.

Heliyon, Journal Year: 2023, Volume and Issue: 9(12), P. e21886 - e21886

Published: Nov. 19, 2023

Genetically modified macrophage infusion has been proven to be a novel treatment for cancer. One of the most important processes in macrophage-based therapy is efficient transfer genes. HIV-1-derived lentiviruses were widely used as delivery vectors chimeric antigen receptor T and NK cell construction. While macrophages are relatively refractory this lentiviral vector transduction result myeloid-specific restriction factor SAMHD1, which inhibited virion cycle through exhausting dNTPs pool degradating RNAs. An strategy developed via packaging HIV-2 accessory protein Vpx into virion. counteracts SAMHD1 CRL4 (DCAF1) E3 ubiquitin ligase mediated degradation, yet influence by introduction on not fully evaluated. Here, we constructed HIV-1-Vpx systematically analyzed infection efficiency time-dependent manner. Our results showed that simplified virus exhibited dramatically enhanced human compared normal lentivirus. Moreover, transcriptome sequencing was performed evaluate cellular status after infection. The indicated promoted remodeling towards proinflammatory phenotype, without affecting classic M1/M2 surface markers. suggest Vpx-containing lentivirus could an ideal tool generation genetically engineered with high gene poised sets, especially solid tumor treatment.

Language: Английский

Citations

16
Epithelial proliferation and cell cycle dysregulation in kidney injury and disease DOI
Kyung Lee, G. Luca Gusella, John Cijiang He

et al.

Kidney International, Journal Year: 2021, Volume and Issue: 100(1), P. 67 - 78

Published: April 6, 2021

Language: Английский

Citations

30
HIV-1 Vpr drives a tissue residency-like phenotype during selective infection of resting memory T cells DOI Creative Commons
Ann‐Kathrin Reuschl, Dejan Mesner, Maitreyi Shivkumar

et al.

Cell Reports, Journal Year: 2022, Volume and Issue: 39(2), P. 110650 - 110650

Published: April 1, 2022

HIV-1 replicates in CD4+ T cells, leading to AIDS. Determining how shapes its niche create a permissive environment is central informing efforts limit pathogenesis, disturb reservoirs, and achieve cure. A key roadblock understanding HIV-T cell interactions the requirement activate cells vitro make them infection. This dramatically alters biology virus-host interactions. Here we show that cell-to-cell spread permits efficient, productive infection of resting memory without prior activation. Strikingly, find primes gain characteristics tissue-resident (TRM), including upregulating surface markers transcription factor Blimp-1 inducing transcriptional program overlapping core TRM signature. reprogramming driven by Vpr requires packaging into virions manipulation STAT5. Thus, reprograms with implications for viral replication persistence.

Language: Английский

Citations

22