Abstract
Ribavirin (RBV) is a synthetic nucleoside analog with broad spectrum antiviral activity. Although RBV is approved for the treatment of hepatitis C virus, respiratory syncytial virus, and Lassa fever virus infections, its mechanism of action and therapeutic efficacy remains highly controversial. Recent reports show that the development of cell-based resistance after continuous RBV treatment via decreased RBV uptake can greatly limit its efficacy. Here, we examined whether certain cell types are naturally resistant to RBV even without prior drug exposure. Seven different cell lines from various host species were compared for RBV antiviral activity against two nonsegmented negative-strand RNA viruses, vesicular stomatitis virus (VSV, a rhabdovirus) and Sendai virus (SeV, a paramyxovirus). Our results show striking differences between cell types in their response to RBV, ranging from virtually no antiviral effect to very effective inhibition of viral replication. Despite differences in viral replication kinetics for VSV and SeV in the seven cell lines, the observed pattern of RBV resistance was very similar for both viruses, suggesting that cellular rather than viral determinants play a major role in this resistance. While none of the tested cell lines was defective in RBV uptake, dramatic variations were observed in the long-term accumulation of RBV in different cell types, and it correlated with the antiviral efficacy of RBV. While addition of guanosine neutralized RBV only in cells already highly resistant to RBV, actinomycin D almost completely reversed the RBV effect (but not uptake) in all cell lines. Together, our data suggest that RBV may inhibit the same virus via different mechanisms in different cell types depending on the intracellular RBV metabolism. Our results strongly point out the importance of using multiple cell lines of different origin when antiviral efficacy and potency are examined for new as well as established drugs in vitro.
Highlights
Ribavirin (RBV, known as virazole), 1-ß-D-ribofuranosyl1,2,4-triazole-3-carboxamide, is the first synthetic, broad-spectrum antiviral nucleoside analog [1], which has been shown to exhibit antiviral activity against many RNA and DNA viruses both in vitro and in vivo [2,3,4,5]
Identification of RBV-resistant cell lines To determine whether ‘‘natural’’ resistance to RBV exists in some cell types, we selected seven commonly used cell lines (BHK21, BSRT7, HeLa, A549, 4T1, HEp2, and Vero) originated from various hosts and tissues, and compared them for the antiviral activity of RBV against VSV and SeV
We compared the antiviral activity of RBV against two prototypic members of the order Mononegavirales, VSV and SeV, in seven different cell lines originated from various hosts and tissues
Summary
Ribavirin (RBV, known as virazole), 1-ß-D-ribofuranosyl1,2,4-triazole-3-carboxamide, is the first synthetic, broad-spectrum antiviral nucleoside analog [1], which has been shown to exhibit antiviral activity against many RNA and DNA viruses both in vitro and in vivo [2,3,4,5]. The mechanism of synergy between RBV and IFN [7,8], which is critical for successful anti-HCV therapy, remains unclear [4]. Despite these successes with RBV/IFN combination therapy resulting in a so called sustained virological response (SVR, no detectable plasma HCV RNA during treatment and for at least 6 months after therapy) or end-of-treatment response (ETR, HCV RNA is undetectable when therapy is terminated), a large portion of patients are ‘‘non-responders’’ (detectable HCV RNA throughout the treatment period). The mechanism of non-response to RBV/IFN treatment is very controversial and, no alternative therapies available for non-responders
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