Abstract The systematic identification of human-virus protein–protein interactions (PPIs) is a critical step toward elucidating the underlying mechanisms of viral infection, directly informing the development of targeted interventions against existing and emerging viral threats. In this work, we presented DeepGNHV, an end-to-end framework that integrated a pretrained protein language model with structural features derived from AlphaFold2 and leveraged graph attention networks to predict human-virus PPIs. In comparison to other state-of-the-art approaches, DeepGNHV exhibited superior predictive performance, especially when applied to viral proteins absent from the training process, indicating its strong generalization capability for detecting newly emerging virus-related PPIs. We further demonstrated DeepGNHV’s robustness across diverse perturbations and its practical application under high-confidence thresholds. Additionally, we conducted extensive predictions of human-HPV PPIs, which were supported by multiple lines of evidence and identified several host factors that specifically interact with high-risk HPV. To further explore the biological significance of DeepGNHV, we provided a case study to pinpoint specific residues that play critical roles in facilitating the corresponding PPIs. The source code of DeepGNHV and related data is publicly available on GitHub (https://github.com/bioboy0415/DeepGNHV).
Jiang et al. (Sun,) studied this question.