Emerging Microbes & Infections, Год журнала: 2024, Номер 13(1)
Опубликована: Сен. 6, 2024
Increased CD4
Язык: Английский
Nature Reviews Microbiology, Год журнала: 2024, Номер 22(6), С. 328 - 344
Опубликована: Фев. 9, 2024
Язык: Английский
Процитировано
28
Cell, Год журнала: 2024, Номер 187(5), С. 1238 - 1254.e14
Опубликована: Фев. 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.
Язык: Английский
Процитировано
12
Journal of the National Cancer Center, Год журнала: 2025, Номер 5(2), С. 221 - 235
Опубликована: Фев. 12, 2025
Язык: Английский
Процитировано
1
Frontiers in Cellular and Infection Microbiology, Год журнала: 2024, Номер 13
Опубликована: Янв. 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
Язык: Английский
Процитировано
6
Life Science Alliance, Год журнала: 2024, Номер 7(10), С. e202402736 - e202402736
Опубликована: Июль 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.
Язык: Английский
Процитировано
6
Current Opinion in HIV and AIDS, Год журнала: 2024, Номер 19(4), С. 169 - 178
Опубликована: Май 1, 2024
Purpose of review Successful sustained remission HIV infection has been achieved after CCR5Δ32/Δ32 allogeneic hematopoietic stem cell transplantation for treatment leukemia in a small cohort people living with (PLWH). This breakthrough demonstrated that the goal curing was achievable. However, high morbidity and mortality associated bone marrow limits routine application this approach provides strong rationale pursuing alternative strategies long-term antiretroviral therapy (ART)-free remission. Notably, immune-mediated control replication observed elite controllers posttreatment suggests potent HIV-specific immune responses could provide ART-free PLWH. The capacity chimeric antigen receptor (CAR)-T cells engineered to target malignant induce cure cancer patients made an attractive PLWH response. Here, we recent advances design anti-HIV CAR-T-cell functional cure. Recent findings reservoirs are established days persist through clonal expansion infected cells. continuous interaction between latently system shapes landscape latency likely contributes viral controllers. CAR-T can exhibit superior antiviral activity as compared native T cells, particularly because they be have multiple specificities, resistance infection, dual costimulatory signaling, checkpoint inhibitors, derivation, CMV TCR coexpression, tissue homing ligands. These modifications significantly improve capacities prevent escape, resist enhance cytotoxicity, persistence, penetration. Collectively, these novel increased their infection. Summary Anti-HIV in-vitro in-vivo function. combination other immunotherapeutics may contribute
Язык: Английский
Процитировано
3
Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(36)
Опубликована: Авг. 27, 2024
In the absence of antiretroviral therapy (ART), a subset individuals, termed HIV controllers, have levels plasma viremia that are orders magnitude lower than non-controllers (NC) who at higher risk for disease progression. addition to having fewer infected cells resulting in with RNA, it is possible controllers due fraction HIV-1 unspliced RNA (HIV usRNA) compared NC. To directly test this possibility, we used sensitive and quantitative single-cell sequencing methods compare contain one or more copies usRNA peripheral blood mononuclear (PBMC) obtained from The containing did not differ between two groups. Rather, were strongly associated total number had usRNA, as reported by others, 34-fold per million PBMC. These results reveal viremic control proviruses expressing unlike what elite but only related overall, maybe reflecting greater immune clearance cells. Our findings show proviral silencing key mechanism will help refine strategies toward achieving remission without ART.
Язык: Английский
Процитировано
3
PLoS Pathogens, Год журнала: 2025, Номер 21(1), С. e1012822 - e1012822
Опубликована: Янв. 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.
Язык: Английский
Процитировано
0
Journal of Virology, Год журнала: 2025, Номер unknown
Опубликована: Фев. 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
Язык: Английский
Процитировано
0
Current HIV/AIDS Reports, Год журнала: 2025, Номер 22(1)
Опубликована: Фев. 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
Язык: Английский
Процитировано
0