Allophycocyanin inhibits HIV-1 gp120 and reverse transcriptase through enthalpy-driven binding and antioxidative protection: integrative computational and experimental insights.

Human immunodeficiency virus type 1 (HIV-1) remains a major global health challenge, underscoring the need for antiviral strategies that extend beyond conventional small-molecule inhibitors. Here, we investigate the cyanobacterial phycobiliprotein allophycocyanin (APC) as a natural macromolecular scaffold with combined antiviral and antioxidant activities. Integrative protein-protein docking and long-timescale molecular dynamics simulations revealed stable APC interactions with HIV-1 gp120, protease, and reverse transcriptase (RT), with gp120 displaying the most favorable binding propensity based on qualitative free-energy ranking and interfacial stability. Isothermal titration calorimetry demonstrated a moderate, enthalpy-driven gp120-APC interaction in solution, consistent with a transient yet biologically relevant protein-protein association. In HIV-1-infected cells, APC treatment reduced viral protein abundance, including gp120, protease, and RT, and significantly inhibited RT enzymatic activity. APC also mitigated infection-induced oxidative stress, restoring redox balance toward basal levels. While computational affinity estimates are semi-quantitative and cellular uptake mechanisms were not directly examined, the combined structural, biophysical, and cellular data support a model in which APC interferes with viral entry and downstream replication while providing host-protective antioxidant effects. Collectively, this study advances APC from a general antioxidant biomolecule to a mechanistically characterized natural macromolecular inhibitor with potential relevance as an adjunctive anti-HIV-1 strategy.