Replication-competent HIV-1 in human alveolar macrophages and monocytes despite nucleotide pools with elevated dUTP DOI Open Access

Junru Cui,

Mesfin Meshesha,

Natela Churgulia

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: May 4, 2022

Abstract Although CD4 + memory T cells are considered the primary latent reservoir for HIV-1, replication competent HIV has been detected in tissue macrophages both animal and human studies. During vitro infection, depleted nucleotide pool high dUTP levels monocyte derived (MDM) leads to proviruses with of dUMP, which implicated viral restriction or reduced transcription depending on uracil base excision repair (UBER) competence macrophage. Incorporated dUMP also DNA from circulating monocytes (MC) alveolar (AM) infected patients antiretroviral therapy (ART), establishing biological relevance this phenotype but not replicative capacity dUMP-containing proviruses. As compared differentiated MDM, AM normal donors had 6-fold lower dTTP a increased dUTP/dTTP, indicating highly restrictive dNTP reverse transcription. Expression glycosylase (UNG) was 8-fold already low MDM. Accordingly, ∼80% contained persisted at least 14-days due UNG activity. Unlike expression SAM HD domain containing deoxynucleoside triphosphate triphosphohydrolase 1 (SAMHD1) over 14 days post-HIV while nucleotidohydrolase decreased. These AM-specific effects suggest response centered excising copies increasing relative levels. Despite pools, we rare AM, peripheral MC, ART-treated donors. findings indicate that potential integration block incorporated is realized during vivo infection MC near absence UBER In addition, SAMHD1 post-infection too slow prevent integration. persists integrated viruses, based studies, can lead transcriptional silencing. This possible silencing outcome persistent could promote latency until repressive reversed.

Language: Английский

CD4 T cell contact drives macrophage cell cycle progression and susceptibility to lentiviral transduction DOI Creative Commons
Petra Mlčochová, Raphael Heilig, Román Fischer

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 16, 2024

Abstract Macrophages are typically quiescent cells residing in G0, though tissue macrophages have been shown to proliferate locally tissues; we previously demonstrated that differentiated monocyte derived (MDM) can be stimulated re-enter G1 phase of the cell cycle from without division. Entry into correlates with an increase CDK1 expression which phosphorylates deoxynucleotide-triphosphate hydrolase SAMHD1 at position 592. not only regulates cellular dNTP levels, but is also a restriction factor for virus replication HIV-1 and DNA viruses. Here show contact autologous CD4 T leads antigen-independent macrophage progression G0-G1, accompanied by associated proteins, including CDK1, activation canonical MEK-ERK pathway. Further, blocked anti-cancer drugs targeting axis such as Palcociclib, pre-treatment EGFR antibody, providing additional evidence surface interactions driving proliferative responses. Cell uninfected renders ten-fold more susceptible transduction VSV-G pseudotyped particles.

Language: Английский

Citations

1
Replication-competent HIV-1 in human alveolar macrophages and monocytes despite nucleotide pools with elevated dUTP DOI Creative Commons

Junru Cui,

Mesfin Meshesha,

Natela Churgulia

et al.

Retrovirology, Journal Year: 2022, Volume and Issue: 19(1)

Published: Sept. 16, 2022

Abstract Background Although CD4 + memory T cells are considered the primary latent reservoir for HIV-1, replication competent HIV has been detected in tissue macrophages both animal and human studies. During vitro infection, depleted nucleotide pool high dUTP levels monocyte derived (MDM) leads to proviruses with of dUMP, which implicated viral restriction or reduced transcription depending on uracil base excision repair (UBER) competence macrophage. Incorporated dUMP also DNA from circulating monocytes (MC) alveolar (AM) infected patients antiretroviral therapy (ART), establishing biological relevance this phenotype but not replicative capacity dUMP-containing proviruses. Results As compared differentiated MDM, AM normal donors had sixfold lower dTTP a increased dUTP/dTTP, indicating highly restrictive dNTP reverse transcription. Expression glycosylase (UNG) was eightfold already low MDM. Accordingly, ~ 80% contained persisted at least 14-days due UNG activity. Unlike expression SAM HD domain containing deoxynucleoside triphosphate triphosphohydrolase 1 (SAMHD1) over 14 days post-HIV while nucleotidohydrolase (DUT) decreased. These AM-specific effects suggest response centered excising copies increasing relative levels. Despite pools, we rare AM, peripheral MC, ART-treated donors. Conclusions findings indicate that potential integration block incorporated is realized during vivo infection MC near absence UBER In addition, SAMHD1 post-infection too slow prevent integration. persists integrated viruses, based studies, can lead transcriptional silencing. This possible silencing outcome persistent could promote latency until repressive reversed.

Language: Английский

Citations

5
HIV-1 Accessory Proteins Impart a Modest Interferon Response and Upregulate Cell Cycle-Related Genes in Macrophages DOI Creative Commons
Laura Martins, Matthew A. Szaniawski, Elizabeth S. C. P. Williams

et al.

Pathogens, Journal Year: 2022, Volume and Issue: 11(2), P. 163 - 163

Published: Jan. 26, 2022

HIV-1 infection of myeloid cells is associated with the induction an IFN response. How manipulates and subverts response key interest for design therapeutics to improve immune function mitigate dysregulation in people living HIV. accessory genes viral fitness by altering host pathways ways that enable transmission occur without interference from We previously described changes transcriptomes infected IFN-stimulated macrophages noted transcription IFN-regulated related cell cycle processes were upregulated during infection. In present study, we sought define roles individual upregulation cycle-related using RNA sequencing. observed Vif induces a set involved mitotic these are potently downregulated upon stimulation type-I -II IFNs. Vpr also was largely responsible inducing attenuated note induced most closely resembled type-III Vpu Nef-regulated smaller sets whose transcriptomic signatures cytokine chemokine processes. This work provides more insight regarding manipulated proteins at transcriptional level.

Language: Английский

Citations

3
Hypoxia Drives HIF2-Dependent Reversible Macrophage Cell Cycle Entry DOI
Bo Meng, Na Zhao, Petra Mlčochová

et al.

Published: Jan. 1, 2024

Download This Paper Open PDF in Browser Add to My Library Share: Permalink Using these links will ensure access this page indefinitely Copy URL DOI

Language: Английский

Citations

0
Macrophage Cell Cycle DOI

Louis Dillac,

Leon El Dika,

Rahim Ullah

et al.

Results and problems in cell differentiation, Journal Year: 2024, Volume and Issue: unknown, P. 119 - 134

Published: Jan. 1, 2024

Language: Английский

Citations

0
Allosteric substrate activation of SAMHD1 shapes deoxynucleotide triphosphate imbalances by interconnecting the depletion and biosynthesis of different dNTPs DOI Creative Commons
Claudia McCown, Corey H. Yu, Dmitri N. Ivanov

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Nov. 14, 2023

SAMHD1 is a dNTPase that impedes replication of HIV-1 in myeloid cells and resting T lymphocytes. Here we elucidate the substrate activation mechanism depends on dNTP binding at allosteric sites concomitant tetramerization enzyme. The study reveals involves an inactive tetrameric intermediate with partial occupancy sites. equilibrium between active states, which coupled to cooperative binding/dissociation least two ligands, controls activity enzyme, which, addition, identity dNTPs occupying four tetramer. We show how such regulation determines deoxynucleotide triphosphate levels established dynamic equilibria production SAMHD1-catalyzed depletion. Notably, enables distinctive functionality SAMHD1, call facilitated depletion, whereby elevated biosynthesis some results more efficient depletion others. regulatory relationship different sheds light emerging role biology homeostasis implications for HIV/AIDS, innate antiviral immunity, cell disorders, telomere maintenance therapeutic efficacy nucleoside analogs.

Language: Английский

Citations

1
Hypoxia drives HIF2-dependent macrophage cell cycle entry and susceptibility to lentiviral transduction DOI Creative Commons
Bo Meng, Na Zhao, Petra Mlčochová

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Dec. 16, 2023

Abstract Macrophages play critical roles across health and disease. Low oxygen conditions (hypoxia) have been associated primarily with cell cycle arrest in cultured dividing cells. are typically quiescent G0, though yolk sac bone marrow derived macrophages frequently proliferate monocyte-derived tissue able to response signals. Here we show that hypoxia (1% tension) results reversible entry into the monocyte (MDM) mouse peritoneal macrophages. Cell progression is largely limited G1/S phase very little G2/M. Mechanistically, this transitioning triggered by a HIF2α-directed transcriptional program. The accompanied increased expression of cycle-associated proteins, including CDK1, activation canonical mitogen-activated MEK-ERK proliferation pathway. CDK1 SAMHD1 phosphorylation at T592 hypoxic renders them hyper-susceptible lentiviral transduction. Furthermore, PHD inhibitors, which activate HIFs, recapitulate HIF2α-dependent macrophages, as well susceptibility Finally, demonstrate tumour (TAM) lung cancers exhibit transcriptomic profiles representing responses low single level. This work uncovers HIF2α driven macrophage culminates high These findings implications for inflammation, neoplasia pathogen defence.

Language: Английский

Citations

1
Harnessing Β-Glucan Conjugated Quercetin Nanocomplex to Function as a Promising Anti-Inflammatory Agent Via Macrophage-Targeted Delivery DOI
Yuting Su, Manting Huang,

Qiaochun Chen

et al.

Published: Jan. 1, 2024

Language: Английский

Citations

0
Harnessing β-glucan conjugated quercetin nanocomplex to function as a promising anti-inflammatory agent via macrophage-targeted delivery DOI
Yuting Su, Manting Huang,

Qiaochun Chen

et al.

Carbohydrate Polymers, Journal Year: 2024, Volume and Issue: 349, P. 122952 - 122952

Published: Nov. 14, 2024

Language: Английский

Citations

0
G2-S16 Polyanionic Carbosilane Dendrimer Can Reduce HIV-1 Reservoir Formation by Inhibiting Macrophage Cell to Cell Transmission DOI Open Access
Ignacio Relaño-Rodríguez, María de la Sierra Espinar-Buitrago,

Vanessa Martín-Cañadilla

et al.

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(16), P. 8366 - 8366

Published: Aug. 4, 2021

Human immunodeficiency virus (HIV-1) is still a major problem, not only in developing countries but also re-emerging several developed countries, thus the development of new compounds able to inhibit virus, either for prophylaxis or treatment, needed. Nanotechnology has provided science community with tools biomedical applications. G2-S16 polyanionic carbosilane dendrimer capable inhibiting HIV-1 vitro and vivo by interacting directly viral particles. One main barriers eradication reservoirs created primoinfection. These reservoirs, mainly T cells, are untargetable actual drugs immune system. Thus, one approach from reaching these reservoir cells. In this context, macrophages play role as they can deliver particles cells establishing reservoirs. We showed that infection infected healthy CD4/CD8 lymphocytes eliminating infectivity inside macrophages, so carry infectious other body locations, preventing forming.

Language: Английский

Citations

3