Dynamics and regulation of nuclear import and nuclear movements of HIV-1 complexes DOI Creative Commons
Ryan C. Burdick, Krista A. Delviks‐Frankenberry, Jian Chen

et al.

PLoS Pathogens, Journal Year: 2017, Volume and Issue: 13(8), P. e1006570 - e1006570

Published: Aug. 21, 2017

The dynamics and regulation of HIV-1 nuclear import its intranuclear movements after have not been studied. To elucidate these essential post-entry events, we labeled viral complexes with two fluorescently tagged virion-incorporated proteins (APOBEC3F or integrase), analyzed the envelope (NE) docking, import, in living cells. We observed that exhibit unusually long NE residence times (1.5±1.6 hrs) compared to most cellular cargos, which are imported into nuclei within milliseconds. Furthermore, requires capsid (CA) pore protein Nup358, results significant loss CA, indicating one core uncoating steps occurs during import. Our showed CA-Cyclophilin A interaction regulates by delaying time docking as well transport through pore, but blocking reverse transcription has no effect on kinetics also visualized translocation docked at nucleus their determined exhibited a brief fast phase (<9 min), followed slow lasting several hours. comparison movement those proviral sites supports hypothesis quickly tether chromatin near integration both wild-type cells LEDGF/p75 was deleted using CRISPR/cas9, tethering interactions do require LEDGF/p75. These studies provide novel insights complex-NE association, uncoating, precede site selection.

Language: Английский

Clinical use of lentiviral vectors DOI Creative Commons
Michael C. Milone, Una O’Doherty

Leukemia, Journal Year: 2018, Volume and Issue: 32(7), P. 1529 - 1541

Published: March 22, 2018

Viral vectors provide an efficient means for modification of eukaryotic cells, and their use is now commonplace in academic laboratories industry both research clinical gene therapy applications. Lentiviral vectors, derived from the human immunodeficiency virus, have been extensively investigated optimized over past two decades. Third-generation, self-inactivating lentiviral recently used multiple trials to introduce genes into hematopoietic stem cells correct primary immunodeficiencies hemoglobinopathies. These also mature T generate immunity cancer through delivery chimeric antigen receptors (CARs) or cloned T-cell receptors. CAR therapies engineered using demonstrated noteworthy success patients with B-cell malignancies leading regulatory approval first genetically cellular vectors. In this review, we discuss several aspects that will be interest clinicians, including overview vector development, current uses viral as cancers, large-scale manufacturing long-term follow-up treated products.

Language: Английский

Citations

705
HIV-1 assembly, release and maturation DOI
Eric O. Freed

Nature Reviews Microbiology, Journal Year: 2015, Volume and Issue: 13(8), P. 484 - 496

Published: June 29, 2015

Language: Английский

Citations

573
Cone-shaped HIV-1 capsids are transported through intact nuclear pores DOI Creative Commons
Vojtěch Žíla, Erica Margiotta, Beata Turoňová

et al.

Cell, Journal Year: 2021, Volume and Issue: 184(4), P. 1032 - 1046.e18

Published: Feb. 1, 2021

Human immunodeficiency virus (HIV-1) remains a major health threat. Viral capsid uncoating and nuclear import of the viral genome are critical for productive infection. The size HIV-1 is generally believed to exceed diameter pore complex (NPC), indicating that has occur prior import. Here, we combined correlative light electron microscopy with subtomogram averaging capture structural status reverse transcription-competent complexes in infected T cells. We demonstrated NPC cellulo sufficient apparently intact, cone-shaped capsids. Subsequent import, detected disrupted empty fragments, replication occurs by breaking open, not disassembly into individual subunits. Our data directly visualize key step enhance our mechanistic understanding life cycle.

Language: Английский

Citations

277
HIV-1 uncoats in the nucleus near sites of integration DOI Creative Commons
Ryan C. Burdick, Chenglei Li, MohamedHusen Munshi

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2020, Volume and Issue: 117(10), P. 5486 - 5493

Published: Feb. 24, 2020

Significance For several decades, retroviral core uncoating has been thought to occur in the cytoplasm coordination with reverse transcription, and while some recent studies have concluded that HIV-1 occurs at nuclear envelope during import, none nucleus. Here, we developed methods study by direct labeling quantification of viral capsid protein associated infectious cores produced transcriptionally active proviruses. We find nuclei infected cells are largely intact uncoat near their integration sites just before integration. These unexpected findings fundamentally change our understanding postentry replication events.

Language: Английский

Citations

255
Structure and Assembly of the Nuclear Pore Complex DOI Open Access
Bernhard Hampoelz, Amparo Andrés‐Pons, Panagiotis L. Kastritis

et al.

Annual Review of Biophysics, Journal Year: 2019, Volume and Issue: 48(1), P. 515 - 536

Published: April 3, 2019

Nuclear pore complexes (NPCs) mediate nucleocytoplasmic exchange. They are exceptionally large protein that fuse the inner and outer nuclear membranes to form channels across envelope. About 30 different components, termed nucleoporins, assemble in multiple copies into an intricate cylindrical architecture. Here, we review our current knowledge of structure nucleoporins how those come together situ. We delineate architectural principles on several hierarchical organization levels, including isoforms, posttranslational modifications, higher-order oligomerization nucleoporin subcomplexes. discuss cells exploit this modularity faithfully NPCs.

Language: Английский

Citations

252
HIV-1 uses dynamic capsid pores to import nucleotides and fuel encapsidated DNA synthesis DOI
David A. Jacques, William A. McEwan,

Laura Hilditch

et al.

Nature, Journal Year: 2016, Volume and Issue: 536(7616), P. 349 - 353

Published: Aug. 1, 2016

Language: Английский

Citations

228
Nuclear pore blockade reveals that HIV-1 completes reverse transcription and uncoating in the nucleus DOI
Adarsh Dharan, Niklas Bachmann,

Sarah Talley

et al.

Nature Microbiology, Journal Year: 2020, Volume and Issue: 5(9), P. 1088 - 1095

Published: June 1, 2020

Language: Английский

Citations

194
HIV-1 nuclear import in macrophages is regulated by CPSF6-capsid interactions at the nuclear pore complex DOI Creative Commons
David Alejandro Bejarano, Ke Peng, Vibor Laketa

et al.

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

Published: Jan. 23, 2019

Nuclear entry of HIV-1 replication complexes through intact nuclear pore is critical for successful infection. The host protein cleavage-and-polyadenylation-specificity-factor-6 (CPSF6) has been implicated in different stages early replication. Applying quantitative microscopy reverse-transcription and pre-integration-complexes (RTC/PIC), we show that CPSF6 strongly recruited to but absent from cytoplasmic RTC/PIC primary human macrophages. Depletion or lack binding led accumulation subviral at the envelope macrophages reduced infectivity. Two-color stimulated-emission-depletion indicated under these circumstances are retained inside undergo CA-multimer dependent clustering adjacent basket. We propose mediated by consecutive Nup153 hexameric CA lattice.

Language: Английский

Citations

185
T‐Cell‐Mimicking Nanoparticles Can Neutralize HIV Infectivity DOI
Xiaoli Wei, Gang Zhang,

Danni Ran

et al.

Advanced Materials, Journal Year: 2018, Volume and Issue: 30(45)

Published: Sept. 25, 2018

Abstract To improve human immunodeficiency virus (HIV) treatment and prevention, therapeutic strategies that can provide effective broad‐spectrum neutralization against viral infection are highly desirable. Inspired by recent advances of cell‐membrane coating technology, herein, plasma membranes CD4 + T cells collected coated onto polymeric cores. The resulting T‐cell‐membrane‐coated nanoparticles (denoted as “TNPs”) inherit cell surface antigens critical for HIV binding, such receptor CCR5 or CXCR4 coreceptors. TNPs act decoys attack neutralize diverting the viruses away from their intended host targets. This decoy strategy, which simulates functions rather than directly suppressing replication machinery, has potential to overcome genetic diversity while not eliciting high selective pressure. In this study, it is demonstrated selectively bind with gp120, a key envelope glycoprotein HIV, inhibit gp120‐induced killing bystander cells. Furthermore, when added viruses, effectively peripheral mononuclear blood human‐monocyte‐derived macrophages in dose‐dependent manner. Overall, leveraging natural functions, show great new agent infection.

Language: Английский

Citations

177
Single HIV-1 Imaging Reveals Progression of Infection through CA-Dependent Steps of Docking at the Nuclear Pore, Uncoating, and Nuclear Transport DOI Creative Commons
Ashwanth C. Francis,

Gregory B. Melikyan

Cell Host & Microbe, Journal Year: 2018, Volume and Issue: 23(4), P. 536 - 548.e6

Published: April 1, 2018

Language: Английский

Citations

171