Variability in HIV-1 transmitted/founder virus susceptibility to combined APOBEC3F and APOBEC3G host restriction
Bibliographic record
Abstract
Several APOBEC3 enzymes restrict HIV-1 by deaminating cytosine to form uracil in single-stranded proviral (-)DNA. However, HIV-1 Vif counteracts their activity by inducing their proteasomal degradation. This counteraction by Vif is incomplete, as evidenced by footprints of APOBEC3-mediated mutations within integrated proviral genomes of people living with HIV-1. The relative contributions of multiple APOBEC3s in HIV-1 restriction are not fully understood. Here, we investigated the activity of co-expressed APOBEC3F and APOBEC3G against HIV-1 Subtype B and Subtype C transmitted/founder viruses. We determined that APOBEC3F interacts with APOBEC3G through its N-terminal domain. We provide evidence that this results in protection of APOBEC3F from Vif-mediated degradation because the APOBEC3F N-terminal domain contains residues required for recognition by Vif. We also found that HIV-1 Subtype C Vifs, but not Subtype B Vifs, were less active against APOBEC3G when APOBEC3F and APOBEC3G were co-expressed. Consequently, when APOBEC3F and APOBEC3G were expressed together in a single cycle of HIV-1 replication, only HIV-1 Subtype C viruses showed a decrease in relative infectivity compared to when APOBEC3G was expressed alone. Inspection of Vif amino acid sequences revealed that differences in amino acids adjacent to conserved sequences influenced the Vif-mediated APOBEC3 degradation ability. Altogether, the data provide a possible mechanism for how combined expression of APOBEC3F and APOBEC3G could contribute to mutagenesis of HIV-1 proviral genomes despite the presence of Vif and provide evidence for variability in the Vif-mediated APOBEC3 degradation ability of transmitted/founder viruses.IMPORTANCEAPOBEC3 enzymes suppress HIV-1 infection by inducing cytosine deamination in proviral DNA but are hindered by HIV-1 Vif, which leads to APOBEC3 proteasomal degradation. Moving away from traditional studies that used lab-adapted HIV-1 Subtype B viruses and singular APOBEC3 enzymes, we examined how transmitted/founder isolates of HIV-1 replicated in the presence of APOBEC3F and APOBEC3G. We determined that APOBEC3F interacts with APOBEC3G through its N-terminal domain and that APOBEC3F, like APOBEC3G, has Vif-mediated degradation determinants in the N-terminal domain. This enabled APOBEC3F to be partially resistant to Vif-mediated degradation. We also demonstrated that Subtype C is more susceptible than Subtype B HIV-1 to combined APOBEC3F/APOBEC3G restriction and identified Vif variations influencing APOBEC3 degradation ability. Importantly, Vif amino acid variation outside of previously identified conserved regions mediated APOBEC3 degradation and HIV-1 Vif subtype-specific differences. Altogether, we identified factors that affect susceptibility to APOBEC3F/APOBEC3G restriction.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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 source (direct Gemma or distilled Codex), 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".