Table 1.

List of the most relevant research papers that report in silico, in vitro, and in vivo experiments where inhibitory effects in viral infection and/or proliferation caused by the presence of Lfs of different origins have been observed.

Lactoferrin	Target Virus	Target of Exposure	Method of Exposure	Antiviral Activity	Reference
hLf/bLf	HIV-1	MT4 cells	MTT assay Time-of-addition assay	Interference with viral adsorption and proliferation	[96]
bLf/bLfcin	HIV-1	SupT1 T/U87-CD4 cells	Preincubation of cells with Lf MTT assay	Blocking of HIV-1 variants that use CXCR4 and CCR5 coreceptors	[97]
bLf	HIV-1	Dendritic cells	Time-of-addition experiments with single-cycle transmission assay Preincubation of cells with Lf	Inhibition of DC-mediated capture and transmission of HIV-1 and bLf-resistant HIV-1 through binding observed between Lf and DC-SIGN receptors	[98]
hLf/bLf	HCMV	Human fetal lung fibroblast cells	MTT assay Time-of-addition assay	Receptor-mediated binding observed to the target cell membrane	[96]
hLf/bLf	HSV-1	Vero cells	Particle agglutination assay Immunofluorescence assay ELISA assay	Inhibition of viral adsorption by blocking cellular receptors and glycans (LDL and HS) and/or viral attachment proteins (Lf in both apo- and holo-form)	[99]
bLf	HSV-1 HSV-2	Vero cells	Immunofluorescence assay ELISA assay	Interference from differently metal-saturated Lf with viral binding to cell surface HS receptors. Possible antiviral activity through the interaction of Lf with the viral envelope	[100]
hLf/bLf	HSV-1 HSV-2	Human embryonic fibroblasts cells Murine L cells and derivatives (gro2C cells and sog9 cells)	Incubation of cells with Lf before viral adsorption and during adsorption and penetration steps Staining with crystal violet	Observed inhibition of HSV-1 infectivity dependent on Lf interaction with cell surface GAG chains of HS and CS Interference of Lf with the binding of viral gC to cell surface HS and/or CS	[101]
bLf	HSV-1	GMK cells	Time-of-addition assay SDS-PAGE, Western and far-Western blot Immunoprecipitation	Lf dose-dependent blocking of viral adsorption by competing for HS cell receptors Cell-to-cell viral spread inhibition caused by interaction of Lf with ICP-5 and VP-16 viral proteins	[102]
hLf/bLf	HSV-2	GMK cells	Staining with crystal violet	Possible blocking of non-GAG virus receptor by bLf Observed interaction between hLf and viral structures present in mutant virus HSV-2 gC-neg1	[103]
hLf	EBV	Primary B cells	Flow cytometry Q-PCR Coimmunoprecipitation SDS-PAGE and Western blot Tissue microarray and immunohistochemistry	Direct binding of Lf to CD21 cell receptors	[104]
hLf/bLf	Poliovirus	Vero cells	Indirect immunofluorescence	Inhibition of viral replication in presence of apo- and holo-Lf Antiviral effects detected with Zinc-saturated Lf when incubated with cells after the viral attachment	[105]
hLf/bLf	HCV	HepG2 cells	Far-Western blot Pull-down assay and immunoprecipitation	Binding of Lf to viral envelope proteins E1/E2	[106]
hLf/bLf	HCV	PH5CH8 cells	Preincubation of viral particles and cells with Lf Nested RT-PCR	Prevention of infection of cells in presence of virus preincubated with Lf	[107]
bLf	HCV	MT-2C T cells	Nested RT-PCR	Inhibition of viral entry to the cells by bLf interacting with HCV after mixing of bLF and HCV inoculum	[108]
rcLf/ncLf	HCV	Huh7.5 cells	Nested RT-PCR Western blot	Direct neutralization effects on the viral particle Prevention of viral entry into cells and inhibition of viral replication in infected cells	[109]
hLf	HCV	Huh-7 cells	Dose-response inhibition assay Immunofluorescence and SDS-PAGE	Inhibition of viral ATPase/Helicase NS3 protein mediated by direct interaction between Lf and allosteric binding site on NS3	[110]
bLf	HAdV	Human epidermoid carcinoma larynx (HEp-2) cells Viral particle	Preincubation of viral particles with Lf SDS-PAGE and Western blot Transmission electron microscopy	Binding of Lf to viral particle and external III and IIIa structural polypeptides	[111]
hLf/hLfcin	HAdV	A549 cells	Fiber knob binding experiments Surface plasmon resonance	Binding of Lfcin to hexon protein of viral capsid	[112]
hLf/bLf	CHV	MDCK cells	Preincubation of viral particles and cells with Lf SDS-PAGE and far-Western blot	Binding of bLf with CHV-binding protein in both apo- and holo-form Anti-viral activity of hLf observed	[113]
bLf	Echovirus	GMK cells	Preincubation of viral particles with Lf Immunofluorescence assay ELISA assay Transmission electron microscopy	Observed interaction of Lf with cell surface glycosaminoglycan chains and viral capsid proteins Prevention of viral genome delivery into cytoplasm	[114]
bLf	EV71	RD and SK-N-SH cells	ELISA assay and indirect fluorescent stain	Binding of Lf to VP1 protein of EV71 and target cells Induction of IFN-α expression in SK-N-SH cells and inhibition of EV71-induced IL-6 production	[115]
bLf	H1N1 Influenza A	MDCK cells	Time-of-addition assay ELISA assay Hemolysis inhibition assay	Lactoferrin binds to hemagglutinin and fusion peptide	[32]
hLf	SARS-CoV-2	RBD region/ACE2 receptor	2D Zernike polynomial expansion	Computational definition of regions of Lf with high affinity towards sialic acid and RBD	[116]
hLf	SARS-CoV-2	RBD region/ACE2 receptor	Biolayer interferometry Latex nanoparticle-enhanced turbidimetry	Binding of Lf with ACE2 and observed inhibiting effects in viral interaction with receptor	[117]