Ancestral reconstruction supports that loss of Nef-mediated T cell modulation coincided with the emergence of pathogenic lentiviruses
Bibliographic record
Abstract
Human immunodeficiency virus type 1 (HIV-1) originated following cross-species transmission of simian immunodeficiency virus (SIV) infecting chimpanzees (SIVcpz). While SIV infection of its natural primate hosts is typically non-pathogenic, SIVcpz/HIV-1 is highly pathogenic. SIV/HIV pathogenesis is influenced by the viral accessory protein Nef, which manipulates several immune factors to facilitate disease progression. Specifically, Nef can modulate T cell activation by downregulating the T cell receptor subunit CD3ζ and the co-stimulatory receptor CD28. Several studies have demonstrated that while Nef downregulates CD28 from the T cell surface, this ability is not completely conserved throughout the SIV/HIV phylogeny. In comparison, Nef-mediated CD3 downregulation is highly conserved in SIV derived from lower-order primates yet completely absent from SIVcpz/HIV-1. Here, we used Nef proteins previously generated via an ancestral reconstruction pipeline, corresponding to common ancestors in the SIV/HIV phylogeny leading to HIV-1 group M, and evaluated their ability to downregulate CD3ζ and CD28 in both expression and transduction systems. We observed that only the ancestral Nef of all primate lentiviruses efficiently downregulated both CD3ζ and CD28, while ancestors along the SIVcpz/HIV-1 lineage failed to downregulate CD3ζ and minimally recovered the ability to downregulate CD28 over time. Furthermore, we showed that the loss of CD3ζ and CD28 downregulation was associated with increased expression of cell surface T cell activation markers and inflammatory cytokines, consistent with a pathogenic infection. Altogether, this study illustrates the evolutionary dynamics of Nef modulation of T cell activation and its impact on pathogenesis in the SIV/HIV lineage.IMPORTANCEWe characterized ancestral Nef proteins derived from the lineage that gave rise to HIV-1 group M. We show that the loss of Nef-mediated CD3ζ and CD28 downregulation occurred in the common ancestor of the SIVcpz/HIV-1 lineage and coincided with increased T cell activation, a hallmark of pathogenicity. Moreover, this suggests that evolutionary changes to Nef-mediated immune modulation contributed to the emergence of pathogenic viruses like HIV-1. Together, these findings support the application of ancestral reconstruction to better understand the functional evolution of viral proteins, particularly in the context of cross-species transmission.
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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 | 0.001 |
| 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 | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".