Characterization of in vitro and in vivo Antiviral Activity of Lactoferrin and Ribavirin upon Hantavirus.

Abstract

ABSTRACT. Mechanisms of anti-hantaviral activities of bovine lactoferrin (LF) and ribavirin (Rbv) were investigated. Hantavirus focus formation at 48 hr was 15% of the control in cells treated with 400 µg/ml LF for 1 hr at 37°C prior to viral infection. Post infection treatment with 100 µg/ml Rbv also inhibited the focus formation to 2.5% of the control. Combined LF pre-and Rbv post-infection treatment completely inhibited focus formation. Viral glycoprotein (G2) and nucleocapsid protein (NP) syntheses were delayed in LF pretreated cells up to 24 hr post infection (hpi) but became comparable to the control by 48 hpi. Further, LF inhibited viral shedding at 24 hpi but did not inhibit shedding after 48 hpi. However, Rbv was able to inhibit synthesis of viral proteins, (+) and (-) strand RNAs also inhibited viral shedding after 24 hr. These results suggest that LF inhibits viral adsorption to cells, while Rbv inhibits viral RNA synthesis. For in vivo trials of LF and Rbv, LF pre-and Rbv post-treatment were evaluated in suckling mice infected with hantavirus, of which 7% survived. LF concentrations of 40 and 160 mg/kg administered prior to viral challenge improved survival rates to 15% and 70%, respectively for single administration and 85% and 94%, respectively, for double administration. Rbv concentrations of 25 and 50 mg/kg gave survival rates of 68% and 81%, respectively. This suggests that both LF and Rbv are efficacious in hantavirus infection in vivo.

Ribavirin Causes Error Catastrophe during Hantaan Virus Replication

“…These results suggested that the mRNA produced from cRNA templates was defective, perhaps in its ability to be translated. These findings are similar to those reported by Murphy et al, who showed that ribavirin inhibits the synthesis of viral proteins and RNA and viral shedding of another hantavirus, Seoul virus, strain SR-11 (16). However, the mechanism of inhibition was not elucidated.…”

Liposomalization of Lactoferrin Enhanced It's Anti-inflammatory Effects via Oral Administration

“…It is considered to be a bioactive milk protein that plays versatile roles in the immune system responses and helps to protect the body from various infections. 5,6) Many studies have already demonstrated that bovine lactoferrin (bLF) features a variety of bioactivities such as anti-bacterial, [6][7][8][9] antiviral, [10][11][12] anti-oxidative, 13) anti-tumor, [14][15][16] anti-inflammatory, [17][18][19][20] immunomodulatory, 21) analgesic 22) and antistress 23) effects. Recently, it has also been reported that oral administration of bLF to patients suffering chronic hepatitis C reduced the amount of hepatitis C virus.…”

Milk Derived Peptides with Immune Stimulating Antiviral Properties

“…This combination therapy also demonstrated significantly increased survival rates in an in vivo mice model, not particularly surprising as lactoferrin inhibits viral adsorption to cells and Ribavirin interferes with viral RNA synthesis [122]. Moreover, the antiviral synergy of lactoferrin/lactoferricin with Cidofovir, Ribavirin, Zidovudine, and Acyclovir as all been well documented against human cytomegalovirus, hepatitis C virus, human immunodeficiency virus 1 and herpes simplex virus, respectively [13,[174][175][176].…”

“…Binding to virus particle and cellular receptor on target cell [74] Hantavirus lactoferrin Binding to cellular molecules; synergistic effect with Ribavirin on inhibiting viral replication [72,122] Vesicular stomatitis virus lactoferrin Induction interferon-/ expression to inhibit viral replication [11] Friend virus complex human lactoferrin Regulation on the myelopoiesis; synergistic effect with interferon- [11,56,57,64] Human papillomavirus human and bovine lactoferrin, human and bovine lactoferricin…”

“…However, this boost in activity could be removed if the cells were subsequently washed with phosphate buffered saline prior to infection [72,122]. These results might be explained by the weak interaction between lactoferrin and other cellular molecules rather than heparan sulphate, as the interaction between lactoferrin and heparan sulphate should withstand phosphate buffered saline washing [80].…”