sncRNA signatures underlying HIV-1 restriction in elite controllers
4 affiliations
- 1AIDS Immunopathology Unit, Centro Nacional de Microbiología, Instituto de Salud Carlos III (ISCIII) , ,
- 2Infectious Diseases Department, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS) , ,
- 3AIDS and HIV Research Group, Institut d´Investigacions August Pi i Sunyer (IDIBAPS) Hospital Clinic, University of Barcelona , ,
- 4Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III , ,
Abstract
Introduction: HIV controllers maintain low viral loads without therapy, offering a natural model for a functional cure. The regulatory role of the small non-coding RNA (sncRNA) transcriptome in CD4+ T cells has been scarcely explored. Our study aimed to characterize the sncRNA and coding RNA landscape in CD4+ T cells from HIV controllers and to assess the potential antiviral activity of key non-coding RNAs.
Methods: We performed sncRNA-Seq and RNA-Seq on CD4+ T cells from elite controllers (ECs, n=10), viremic controllers (n=6), and untreated (n=8) and treated (n=9) non-controllers. Differential expression analysis, miRNA-mRNA correlation, interaction mapping, and functional annotation were conducted. To assess antiviral activity, inhibitors for candidate miRNAs were transfected into CEM-NKR.CCR5 cells, which were then infected with a replication-competent HIV-1 clone.
Results: The sncRNA compartment of elite controllers was distinct, including overexpression of specific transfer RNA (tRNA)-Lys isoacceptors and a cluster of five PIWI-interacting RNAs (piRNA) associated with tRNA-Lys genomic repeats. Noteworthy, miR-99b-5p and miR-125a-5p were significantly downregulated in elite controllers compared to both non-controller groups. Concurrently, the coding transcriptome of elite controllers displayed an enrichment in p53 signaling, inflammatory response, cell activation, and oxidative stress. Several genes upregulated in these processes (e.g., THBS1, DPM2) were identified as validated targets of miR-99b-5p and miR-125a-5p. Finally, in vitro experiments showed that miR-99b-5p and miR-125a-5p inhibition, individually or in combination, reduced viral replication by 17.6%, 16.3%, and 21.4%, respectively.
Discussion: Elite controllers exhibit a distinctive sncRNA signature in CD4+ T cells. The coordinated downregulation of miR-99b-5p and miR-125a-5p may contribute to a restrictive cellular environment and reducing viral replication, revealing a novel layer of post-transcriptional regulation in natural HIV control. These findings underscore these miRNAs and their potentially regulated counterparts as potential targets for future therapeutic strategies.
Related
- Plasma Proteomic Profiling Identifies a Subset of HIV Elite Controllers with Inflammatory Profiles Resembling People Without HIV
- Mapping brain networks underlying abstract perceptual decision formation and its EEG signatures
- Transient noradrenergic signals act as online controllers of perceptual computation
- Multi-Trait Characterization and Selection of Elite Wild Kiwifruit (Actinidia spp.) Germplasm from the Dabie Mountains of Hubei, China
- A multi‐race blast resistance locus identified and validated in US elite rice via association and biparental mapping
BibTeX
@article{ayalasuarez2026sncrna,
title = {{sncRNA signatures underlying HIV-1 restriction in elite controllers}},
author = {Rubén Ayala-Suárez and Erick De la Torre Tarazona and Mercedes Bermejo and Manel E. Bargalló and María José Maleno and Mayte Coiras and Lorna Leal and Felipe García and Montserrat Plana and Javier García-Pérez and José Alcamí and Francisco Díez-Fuertes},
journal = {Frontiers in cellular and infection microbiology},
year = {2026},
month = oct,
doi = {10.3389/fcimb.2026.1926123},
url = {https://europepmc.org/article/PMC/PMC13727583},
note = {CC BY},
}
RIS
TY - JOUR
TI - sncRNA signatures underlying HIV-1 restriction in elite controllers
AU - Rubén Ayala-Suárez
AU - Erick De la Torre Tarazona
AU - Mercedes Bermejo
AU - Manel E. Bargalló
AU - María José Maleno
AU - Mayte Coiras
AU - Lorna Leal
AU - Felipe García
AU - Montserrat Plana
AU - Javier García-Pérez
AU - José Alcamí
AU - Francisco Díez-Fuertes
PY - 2026
DA - 2026/10/20
JO - Frontiers in cellular and infection microbiology
DO - 10.3389/fcimb.2026.1926123
UR - https://europepmc.org/article/PMC/PMC13727583
AB - Introduction: HIV controllers maintain low viral loads without therapy, offering a natural model for a functional cure. The regulatory role of the small non-coding RNA (sncRNA) transcriptome in CD4+ T cells has been scarcely explored. Our study aimed to characterize the sncRNA and coding RNA landscape in CD4+ T cells from HIV controllers and to assess the potential antiviral activity of key non-coding RNAs. Methods: We performed sncRNA-Seq and RNA-Seq on CD4+ T cells from elite controllers (ECs, n=10), viremic controllers (n=6), and untreated (n=8) and treated (n=9) non-controllers. Differential expression analysis, miRNA-mRNA correlation, interaction mapping, and functional annotation were conducted. To assess antiviral activity, inhibitors for candidate miRNAs were transfected into CEM-NKR.CCR5 cells, which were then infected with a replication-competent HIV-1 clone. Results: The sncRNA compartment of elite controllers was distinct, including overexpression of specific transfer RNA (tRNA)-Lys isoacceptors and a cluster of five PIWI-interacting RNAs (piRNA) associated with tRNA-Lys genomic repeats. Noteworthy, miR-99b-5p and miR-125a-5p were significantly downregulated in elite controllers compared to both non-controller groups. Concurrently, the coding transcriptome of elite controllers displayed an enrichment in p53 signaling, inflammatory response, cell activation, and oxidative stress. Several genes upregulated in these processes (e.g., THBS1, DPM2) were identified as validated targets of miR-99b-5p and miR-125a-5p. Finally, in vitro experiments showed that miR-99b-5p and miR-125a-5p inhibition, individually or in combination, reduced viral replication by 17.6%, 16.3%, and 21.4%, respectively. Discussion: Elite controllers exhibit a distinctive sncRNA signature in CD4+ T cells. The coordinated downregulation of miR-99b-5p and miR-125a-5p may contribute to a restrictive cellular environment and reducing viral replication, revealing a novel layer of post-transcriptional regulation in natural HIV control. These findings underscore these miRNAs and their potentially regulated counterparts as potential targets for future therapeutic strategies.
SN - 2235-2988
ER -