Exploring the Relationship Between Extracellular Vesicles, the Dendritic Cell Immunoreceptor and MicroRNA-155 in an In Vivo Model of HIV-1 Infection to Understand the Disease and Develop New Treatments
Notice bibliographique
Résumé
Abstract HIV-1 infection induces persistent immune system activation despite antiretroviral therapy. New immunomodulatory targets might be required to restore immune competence. The dendritic cells immunoreceptor (DCIR) can bind HIV-1 and regulate immune functions and extracellular vesicles (EVs) production. EVs have emerged as biomarkers and a non-invasive tool to monitor HIV-1 progression. In people living with HIV-1, an increase in the size and abundance of EVs is associated with a decline in the CD4/CD8 T cells ratio, a key marker of immune dysfunction. Analysis of host nucleic acids within EVs has revealed an enrichment of microRNA-155 (miR-155) during HIV-1 infection. Experiments have demonstrated that miR-155-rich EVs enhance HIV-1 infection in vitro. A humanized NSG-mice model was established to assess the in vivo impact of miR-155-rich EVs. Co-production of virus with miR-155-rich EVs heightened the viral load and lowered the CD4/CD8 ratio in the mice. Upon euthanasia, EVs were isolated from plasma for size and quantity assessment. Consistent with findings in individuals with HIV-1, increased EVs size and abundance were inversely correlated with the CD4/CD8 ratio. Next, by using the more closely related physiological virus co-product with EV-miR-155, we tested a DCIR inhibitor to limit infection and immune damage in a humanized mouse model. DCIR inhibition reduced infection and partially restored immune functions. Finally, viral particles and various EV subtypes can convey HIV-1 RNA. HIV-1 RNA was predominantly associated with large EVs (200-1000nm) rather than small EVs (50-200nm). Viral loads in large EVs strongly correlated with blood and tissue markers of immune activation. The humanized mice model has proven its applicability to studying the roles of EVs on HIV-1 infection and investigating the impact of DCIR inhibition. Author Summary Despite more than 40 years of research, HIV remains a threat to public health around the world. People living with HIV are efficiently treated with antiretroviral therapy, but damage to the immune system persists and the causes remain unknown. Extracellular vesicles allow material, such as microRNA, to transfer between cells. Here, we evaluated the impact of one microRNA, microRNA-155, transported by extracellular vesicles, on HIV infection. Mice were grafted with a human immune system to allow infection by HIV. We showed that extracellular vesicles carrying microRNA-155 amplified mice infection. Extracellular vesicles also reflect the state of their cell of origin. Their analysis can reveal biomarkers to monitor HIV infection. Thus, HIV viral load was quantified in purified extracellular vesicles. We found that the measurement of HIV viral load in purified EVs is a more precise biomarker of disease progression than the traditional plasma viral load. Additionally, potential treatments like DCIR inhibitors improve our ability to manage HIV-1 by restoring the CD4/CD8 ratio, a critical element of the infection process. Overall, our study highlighted the importance of extracellular vesicle cargo in a humanized mouse model of HIV-1 infection, as well as the potential of targeting DCIR to restore the immune response. Highlights MicroRNA-155 promotes HIV-1 infection of humanized NSG mice Abundance and size of total plasmatic EVs are biomarkers of immune dysfunction associated with HIV-1 infection DCIR inhibition limits HIV-1 infection of humanized NSG mice and attenuates immune impairment HIV-1 RNA enrichment in large EVs was associated with biomarkers of immune activation and dysfunction
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,002 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».