Immune evasion mechanisms by HIV-1
Bibliographic record
Abstract
Induction of the innate immune response by viral pathogens is characterized by a rapid production of Type I interferons (IFNβ/α). Recognition of viral components by Toll-like receptors (TLRs) or RIG-I-like receptors (RLRs), initiates multiple intracellular signalling cascades that culminate in the activation of the transcription factor NF-ï«B and the interferon regulatory factors-3 and 7 (IRF-3 and IRF-7). As a consequence, these events lead to the production of immunoregulatory molecules, including Type I IFNs, pro-inflammatory cytokines and IFN-stimulated genes (ISGs), resulting in the inhibition of virus replication. Throughout evolution, viruses have developed strategies to subvert the innate immune response for their own benefit. Human immunodeficiency virus type-1 (HIV-1), the etiological agent of the acquired immunodeficiency syndrome (AIDS), has been shown to evade the innate immune response, resulting in disease progression. Thus, understanding the distinct mechanisms by which HIV-1 modulates TLRs and RLRs signaling pathways will ultimately lead to the development of novel strategies to inhibit HIV-1 replication and propagation. Studies have indicated that TLRs that signal via NF-ï«B enhance HIV-1 replication. However, TLR4 stimulation triggers both NF-ï«B and the IFN pathway and thus may have inhibitory effects on HIV-1 replication. Our first study was aimed at better understanding the role of TLR4 in HIV-1 replication. Therefore, we first characterized IRF-3 and IRF-7 activation following TLR4 stimulation. Our results demonstrate that the non-canonical TBK1 and IKKε are activated with distinct kinetics resulting in the activation of IRF-3 and subsequent induction of Type I IFNs. Thus, activation of the IFN pathway via TLR4 stimulation can provide a novel strategy to inhibit HIV-1 replication. Our second study sought to further delineate the different signaling pathways activated by HIV-1. Accordingly, transcriptional changes induced by distinct HIV-1 subtypes in immature dendritic cells were examined by microarray analysis. Our findings demonstrate that during the late phase of HIV-1 infection, a subset of genes is differentially regulated by the subtypes. In addition, this study highlights the important role of immature dendritic cells in HIV-1 replication and dissemination. Finally, given the importance of RLRs in the recognition of RNA viruses, the objective of the final study was aimed at investigating the evasion mechanisms employed by HIV-1 to counteract the initial antiviral response. Our results reveal that HIV-1 RNA is detected by the cytosolic receptor RIG-I. However, the HIV-1 viral protease sequesters RIG-I to the lysosomes and thus inhibits RIG-I-mediated antiviral response. Overall, the research presented in this thesis provides new avenues for developing novel therapeutic and preventive strategies to combat HIV-1/AIDS.
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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 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.002 | 0.003 |
| Insufficient payload (model declined to judge) | 0.029 | 0.020 |
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; both teacher heads agree on what is shown here.
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".