Emerging Microbes & Infections, Journal Year: 2024, Volume and Issue: 13(1)
Published: Sept. 6, 2024
Increased CD4
Language: Английский
Nature Reviews Microbiology, Journal Year: 2024, Volume and Issue: 22(6), P. 328 - 344
Published: Feb. 9, 2024
Language: Английский
Citations
29
Cell, Journal Year: 2024, Volume and Issue: 187(5), P. 1238 - 1254.e14
Published: Feb. 1, 2024
CD4+ T cells with latent HIV-1 infection persist despite treatment antiretroviral agents and represent the main barrier to a cure of infection. Pharmacological disruption viral latency may expose HIV-1-infected host immune activity, but clinical efficacy latency-reversing for reducing persistence remains be proven. Here, we show in randomized-controlled human trial that histone deacetylase inhibitor panobinostat, when administered combination pegylated interferon-α2a, induces structural transformation reservoir cell pool, characterized by disproportionate overrepresentation proviruses integrated ZNF genes chromatin regions reduced H3K27ac marks, molecular target sites panobinostat. By contrast, near marks were actively selected against, likely due increased susceptibility These data suggest can increase immunological vulnerability accelerate selection epigenetically privileged proviruses.
Language: Английский
Citations
13
Journal of the National Cancer Center, Journal Year: 2025, Volume and Issue: 5(2), P. 221 - 235
Published: Feb. 12, 2025
Language: Английский
Citations
1
Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16
Published: April 11, 2025
The ‘shock and kill’ approach to an HIV cure involves the use of latency reversing agents (LRAs) reactivate latent HIV, with aim induce death infected cells through virus induced cytolysis or immune mediated clearance. Most LRAs tested date have been unable overcome blocks transcription elongation splicing that persist in resting CD4+ T cells. Furthermore, most target host factors therefore associated toxicities. Therefore, there remains a high need for HIV-specific can also potently upregulate expression multiply-spliced RNA viral protein. Transactivator Transcription (Tat) protein plays important role replication - amplifying from promoter but it is present at low negligible levels latently As such, has hypothesized providing Tat trans could result efficient reactivation latency. Recent studies exploring different types Tat-based used nanoparticles delivery describe potent, induction ex vivo. However, are several potential challenges using as therapeutic, including ability cause systemic toxicities vivo , limited reservoir due poor uptake nucleic acid by cells, activating truly transcriptionally silent viruses. Identifying ways mitigate these will be critical developing effective LRA approaches towards cure.
Language: Английский
Citations
1
Frontiers in Cellular and Infection Microbiology, Journal Year: 2024, Volume and Issue: 13
Published: Jan. 11, 2024
Purpose Corneal infections are a leading cause of visual impairment and blindness worldwide. Here we applied high-resolution transcriptomic profiling to assess the general pathogen-specific molecular cellular mechanisms during human corneal infection. Methods Clinical diagnoses herpes simplex virus (HSV) (n=5) bacterial/fungal keratitis were confirmed by histology. Healthy corneas (n=7) keratoconus (n=4) samples served as controls. Formalin-fixed, paraffin-embedded (FFPE) specimens analyzed using 3’ RNA sequencing method Massive Analysis cDNA Ends (MACE RNA-seq). The host response was investigated comprehensive bioinformatic deconvolution (xCell CYBERSORTx) analyses integration with published single cell RNA-seq data cornea. Results Our analysis identified 216 561 genes, that specifically overexpressed in viral or keratitis, respectively, allowed distinguish two etiologies. virus-specific driven adaptive immunity associated signaling pathways, whereas bacterial/fungal-specific mainly involved innate pathways types. We several genes infectious including CXCL9, CXCR3, MMP9 for viral, S100A8/A9, MMP9, IL17 pathway keratitis. Conclusions High-resolution provides new insights into Pathogen-specific profiles may provide foundation novel diagnostic biomarker therapeutic approaches target inflammation-induced damage cells goal improve outcome
Language: Английский
Citations
6
Life Science Alliance, Journal Year: 2024, Volume and Issue: 7(10), P. e202402736 - e202402736
Published: July 26, 2024
The presence of HIV in sequestered reservoirs is a central impediment to functional cure, allowing persist despite life-long antiretroviral therapy (ART), and driving variety comorbid conditions. Our understanding the latent reservoir nervous system incomplete, because difficulties accessing human tissues. Microglia contribute reservoirs, but molecular phenotype HIV-infected microglia poorly understood. We leveraged unique "Last Gift" rapid autopsy program, which people with are closely followed until days or even hours before death. Microglial populations were heterogeneous regarding their gene expression profiles showed similar chromatin accessibility landscapes. Despite ART, we detected occasional containing cell-associated RNA DNA integrated into open regions host's genome (∼0.005%). detectable an inflammatory phenotype. These results demonstrate distinct myeloid cell brains suppressive ART. Strategies for curing neurocognitive impairment will need consider compartment be successful.
Language: Английский
Citations
6
PLoS Pathogens, Journal Year: 2025, Volume and Issue: 21(1), P. e1012822 - e1012822
Published: Jan. 10, 2025
Identifying cellular and molecular mechanisms maintaining HIV-1 latency in the viral reservoir is crucial for devising effective cure strategies. Here we developed an innovative flow cytometry-fluorescent situ hybridization (flow-FISH) approach direct ex vivo detection without need reactivation using a combination of probes detecting abortive elongated transcripts. Our flow-FISH assay distinguished between HIV-1-infected CD4+ T cells expressing or transcripts PBMC from untreated ART-treated PWH Amsterdam Cohort Studies. This method was employed to isolate five ART-naïve transcriptomic analysis by 3’ RNA sequencing. Supervised cluster identified several differentially expressed mitochondrial genes infected with compared containing Notably, enhancing function induced transcription PWH. data strongly suggests that metabolism involved show improving functions induces transcriptional activity These findings underline relevance metabolic regulation infection, support development strategies modulating immunometabolism target latency.
Language: Английский
Citations
0
Journal of Virology, Journal Year: 2025, Volume and Issue: unknown
Published: Feb. 4, 2025
ABSTRACT HIV persists in people living with (PLHIV) on antiretroviral therapy (ART) long-lived and proliferating latently infected CD4+ T cells that selectively express pro-survival proteins, including the zinc finger Ikaros Aiolos. In this study, we investigated whether pomalidomide, an immunomodulatory agent induces degradation of Aiolos, could increase death HIV-infected and/or reverse latency. Using vitro model a green fluorescent protein (GFP) reporter virus, pomalidomide increased expression B cell lymphoma (Bcl)-2 did not apoptosis GFP+ productively cells. Pomalidomide also CD155 UL16-binding (ULBP) stress proteins cells, but translate to enhanced clearance following co-culture natural killer (NK) line. from PLHIV ART, ex vivo activated memory resulting elevated HLA-DR induced proliferation only presence receptor stimulation anti-CD3 anti-CD28. There was no effect cell-associated RNA or frequency intact DNA. conclusion, despite expression, promoting Aiolos using directly induce latency reversal. IMPORTANCE People require lifelong due persistence The have recently been implicated effects imide drug reversal suppressive therapy, as well productive infection, found activation evidence selective
Language: Английский
Citations
0
Current HIV/AIDS Reports, Journal Year: 2025, Volume and Issue: 22(1)
Published: Feb. 4, 2025
Abstract Purpose of Review Despite suppressive antiretroviral therapy (ART), HIV-1 reservoirs persist in various cell types and tissues reignite active replication if is stopped. Persistence the viral people with (PWH) main obstacle to achieving a cure. Identification characterization cellular tissue thus central cure research. Here, we discuss emerging insights into phenotype reservoir cells. Recent Findings persists multiple tissues, anatomic locations, types. Although contributions different CD4 + T-cell subsets are not equal, all harbor part reservoir. A number putative markers have been proposed, such as immune checkpoint molecules, integrins, pro-survival factors. CD32a expression was shown be associated very prominent enrichment DNA, although this finding has challenged. technological advances allow unbiased single-cell phenotypic analyses cells harbouring total or intact proviruses. Summary reported by several independent studies enriched on Expression some these could mechanistically linked persistence, they for instance shield from recognition promote their survival. However, so far no single marker, combination markers, can effectively distinguish HIV-infected uninfected identify
Language: Английский
Citations
0
bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown
Published: Feb. 8, 2025
Abstract HIV infection exerts profound and long-lasting neurodegenerative effects on the central nervous system (CNS) that can persist despite antiretroviral therapy (ART). Here, we used single-nucleus multiome sequencing to map transcriptomic epigenetic landscapes of postmortem human brains from 13 healthy individuals 20 with who have a history treatment ART. Our study spanned three distinct regions—the prefrontal cortex, insular ventral striatum—enabling comprehensive exploration region-specific cross-regional perturbations. We found widespread persistent HIV-associated transcriptional alterations across multiple cell types. Detailed analyses microglia revealed state changes marked by immune activation metabolic dysregulation, while integrative multiomic profiling astrocytes identified subpopulations, including reactive subpopulation unique HIV-infected brains. These findings suggest cells people exhibit molecular shifts may underlie ongoing neuroinflammation CNS dysfunction. Furthermore, cell–cell communication uncovered dysregulated pro-inflammatory interactions among glial populations, underscoring multifaceted enduring impact brain milieu. Collectively, our atlas reveals states signatures signaling providing framework for developing targeted therapies neurological
Language: Английский
Citations
0