A novel synergistic phycobiliprotein combination against HIV-1 shows potent antiviral activity.

Human immunodeficiency virus type 1 (HIV-1) remains a major global public health challenge due to lifelong persistence, latency, and the emergence of drug resistance. Natural bioactive compounds are increasingly being explored as alternative or adjunct antiviral strategies. In this study, we evaluated the antiviral efficacy and cytotoxicity of a synergistic pharmaceutical composition comprising three phycobiliproteins: C-phycocyanin (C-PC), B-phycoerythrin (B-PE), and allophycocyanin (APC), derived from cyanobacteria and marine algae. Individual and combinatorial effects were assessed against HIV-1 using TZM-bl cells and peripheral blood mononuclear cells (PBMCs). A Box-Behnken experimental design was employed to identify optimal synergistic ratios. Among fifteen combinations initially screened at a fixed concentration of 50 µg/mL, five exhibited strong antiviral activity. The optimized formulation (CBA: C2; 73.28% C-PC, 20.70% B-PE, and 6.02% APC) produced up to ~ 100% inhibition of HIV-1 during the screening assay. Subsequent dose-response analyses demonstrated IC50 values ranging from 5.01 to 12.60 µg/mL across different antiviral assays, while exhibiting minimal cytotoxicity (CC50: 577.56 ± 34.5 µg/mL in TZM-bl cells and 247.64 ± 25.49 µg/mL in PBMCs). The formulation showed a high selectivity index, indicating a favourable therapeutic window. These findings highlight the potential of phycobiliprotein-based synergistic formulations as promising candidates for the development of safe and effective anti-HIV-1 therapeutics.