The PKR/PACT response pathway is altered during HIV-1 infection
Bibliographic record
Abstract
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.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".