The PKR/PACT response pathway is altered during HIV-1 infection
Notice bibliographique
Résumé
The interferon response pathway is an important antiviral mechanism. Protein Kinase RNA-activated (PKR) is an Interferon-Stimulated Gene (ISG) activated by double-stranded RNA (dsRNA), such as the TAR RNA structure from HIV. PKR is one of the most studied ISGs and an efficient HIV suppressor. PKR phosphorylates the translation initiation factor eIF2a, resulting in the inhibition of cellular and viral protein synthesis and a block in viral replication. During HIV infection, our lab has shown that PKR is activated at the beginning of infection in Jurkat cells followed by a deactivation when the virus replicates. This is in part attributed to the inhibition of PKR by dsRNA-binding proteins (dsRBP) such as the TAR RNA binding protein (TRBP) and Adenosine deaminase acting on RNA (ADAR1). In addition, we recently found that another dsRBP and a PKR activator, PACT, becomes a PKR inhibitor in HIV-infected cells. Our central hypothesis in the laboratory is that the regulation of PKR activation by dsRNA-binding proteins is critical for HIV to evade the innate immune response. Our objectives for this project were to answer these questions: 1) What is the activation status of PKR in HIV-infected Peripheral Blood Mononuclear Cells (PBMCs)? and 2) What changes PACT from a PKR activator to a PKR inhibitor during HIV infection?1) PKR activation status in HIV-infected PBMCs: We observed a PKR induction and activation at the beginning of infection, followed by a deactivation when HIV replication increased. When IFN a/b was added to HIV-infected PBMCs, PKR activation was restored. This suggests that cells are able to activate PKR but this activation is blocked during HIV infection. Furthermore, PKR activation was moderately increased in HIV-infected untreated patients compared to HIV-infected successfully treated patients. This further increases the importance of PKR during HIV-1 infection 2) Mechanism that alters PACT's function in HIV-infected cells: In contrast to its previously described function, when PACT was overexpressed in HIV-transfected HEK293T cells, PKR activation was inhibited and HIV expression was increased. We found that PACT-mediated increase in HIV-1 expression and production required the presence of PKR. Furthermore, PACT overexpression led to its incorporation in HIV-1 virions and altered Gag processing and HIV Env protein expression. In addition, we tested HIV-1 infectivity in TZM-bl cells and observed a decrease of infectivity in HIV-1 virions produced from PACT and HIV-1 transfected HEK293T cells. In a proteomic screen, we found that HIV-1 expression led to a complete change of PACT interactome when compared to PACT- interacting partners in mock transfected HEK293T cells. In conclusion, the PKR/PACT response pathway is targeted during HIV-1 infection. PKR activation is not sustained and is inhibited by PACT, a PKR activator that switches its function to a PKR inhibitor during HIV-1 infection. In addition, HIV-1 induces a complete change in PACT interactome which might explain PACT's change of function. Understanding PKR regulation by HIV could aid in understanding viral persistence.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,001 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,001 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 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 tête enseignante, 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 ».