Conformational dynamics of the HIV-1 envelope glycoprotein from CRF01_AE is associated with susceptibility to antibody-dependent cellular cytotoxicity
Bibliographic record
Abstract
ABSTRACT The HIV-1 envelope glycoprotein (Env) is expressed at the surface of infected cells and, as such, can be targeted by non-neutralizing antibodies (nnAbs) that mediate antibody-dependent cellular cytotoxicity (ADCC). Previous single-molecule Förster resonance energy transfer (smFRET) studies demonstrated that Envs from clinical isolates predominantly adopt a “closed” conformation (State 1), which is resistant to nnAbs. After interacting with the cellular receptor CD4, the conformational equilibrium of Env shifts toward States 2 and 3, exposing the coreceptor-binding site (CoRBS) and permitting targeting by CD4-induced (CD4i) antibodies. We showed that the binding of anti-CoRBS Abs enables the engagement of other nnAbs that target the cluster A epitopes on Env. Anti-cluster A nnAbs stabilize an asymmetric Env conformation, State 2A, and have potent ADCC activity. CRF01_AE strains were suggested to be intrinsically susceptible to ADCC mediated by nnAbs. This may be due to the presence of a histidine at position 375, known to shift Env toward more “open” conformations. In this work, through adaptation of an established smFRET imaging approach, we report that native, unliganded CRF01_AE HIV-1 Envs frequently sample the State 2A conformation. This is in striking contrast with Envs from clades A and B, for example HIV-1 JR-FL , which do not transition to State 2A in the absence of ligands. These findings inform on the conformational dynamics of CRF01_AE Env, which are relevant for structure-based design of both synthetic inhibitors of receptor binding and enhancers of ADCC as therapeutic alternatives. IMPORTANCE A concerning increase in infections with HIV-1 from CRF01_AE has occurred globally and regionally in recent years, especially in Southeast Asia. Despite the advances made in understanding HIV-1 envelope glycoprotein (Env) conformational dynamics, the knowledge about Env from CRF01_AE HIV-1 is limited. Here, we demonstrate that the unliganded CRF01_AE Env readily samples an “open” conformation (State 2A), which is susceptible to antibody-dependent cellular cytotoxicity (ADCC). This is in contrast with the subtypes previously studied from HIV-1 group M that rely on anti-cluster A antibodies to adopt State 2A. These findings are relevant for the structure-based design of novel synthetic inhibitors of CD4 binding and enhancers of ADCC for the elimination of infected cells.
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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".