Histidine 375 Modulates CD4 Binding in HIV-1 CRF01_AE Envelope Glycoproteins
Bibliographic record
Abstract
The envelope glycoproteins (Envs) from human immunodeficiency virus type 1 (HIV-1) mediate viral entry. The binding of the HIV-1 gp120 glycoprotein to CD4 triggers conformational changes in gp120 that allow high-affinity binding to its coreceptors. In contrast to all other Envs from the same phylogenetic group, M, which possess a serine (S) at position 375, those from CRF01_AE strains possess a histidine (H) at this location. This residue is part of the Phe43 cavity, where residue 43 of CD4 (a phenylalanine) engages with gp120. Here we evaluated the functional consequences of replacing this residue in two CRF01_AE Envs (CM244 and 92TH023) by a serine. We observed that reversion of amino acid 375 to a serine (H375S) resulted in a loss of functionality of both CRF01_AE Envs as measured by a dramatic loss in infectivity and ability to mediate cell-to-cell fusion. While no effects on processing or trimer stability of these variants were observed, decreased functionality could be linked to a major defect in CD4 binding induced by the replacement of H375 by a serine. Importantly, mutations of residues 61 (layer 1), 105 and 108 (layer 2), and 474 to 476 (layer 3) of the CRF01_AE gp120 inner domain layers to the consensus residues present in group M restored CD4 binding and wild-type levels of infectivity and cell-to-cell fusion. These results suggest a functional coevolution between the Phe43 cavity and the gp120 inner domain layers. Altogether, our observations describe the functional importance of amino acid 375H in CRF01_AE envelopes. IMPORTANCE: A highly conserved serine located at position 375 in group M is replaced by a histidine in CRF01_AE Envs. Here we show that H375 is required for efficient CRF01_AE Env binding to CD4. Moreover, this work suggests that specific residues of the gp120 inner domain layers have coevolved with H375 in order to maintain its ability to mediate viral entry.
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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 | 0.000 | 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".