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Interferon impedes an early step of hepatitis delta virus infection.

Han Z, Nogusa S, Nicolas E, Balachandran S, Taylor J - PLoS ONE (2011)

Bottom Line: Similarly, this study shows that even when an interferon response was induced by transfection of poly(IC) into a cell line, HDV RNA accumulation was only modestly inhibited.These interferon treatments were shown to produce significant time-dependent increases of host response proteins such as for Stat-1, phosphoStat-1, Mx1/2/3 and PKR, and yet interferon pretreatment of hepatocytes did not confer an increased inhibition of HDV replication over interferon treatment at the time of (or after) infection.These and other data support the interpretation that interferon action against HDV replication can occur and is largely mediated at the level of entry into primary human hepatocytes.

View Article: PubMed Central - PubMed

Affiliation: Fox Chase Cancer Center, Philadelphia, Pennsylvania, United States of America.

ABSTRACT
Hepatitis delta virus (HDV) infects hepatocytes, the major cell type of the liver. Infection of the liver may be either transient or chronic. The prognosis for patients with chronic HDV infection is poor, with a high risk of cirrhosis and hepatocellular carcinoma. The best antiviral therapy is weekly administration for at least one year of high doses of interferon alpha. This efficacy of interferon therapy has been puzzling in that HDV replication in transfected cell lines is reported as insensitive to administration of interferon alpha or gamma. Similarly, this study shows that even when an interferon response was induced by transfection of poly(IC) into a cell line, HDV RNA accumulation was only modestly inhibited. However, when the HDV replication was initiated by infection of primary human hepatocytes, simultaneous addition of interferons alpha or gamma at 600 units/ml, a concentration comparable to that achieved in treated patients, the subsequent HDV RNA accumulation was inhibited by at least 80%. These interferon treatments were shown to produce significant time-dependent increases of host response proteins such as for Stat-1, phosphoStat-1, Mx1/2/3 and PKR, and yet interferon pretreatment of hepatocytes did not confer an increased inhibition of HDV replication over interferon treatment at the time of (or after) infection. These and other data support the interpretation that interferon action against HDV replication can occur and is largely mediated at the level of entry into primary human hepatocytes. Thus in vivo, the success of long-term interferon therapy for chronic HDV, may likewise involve blocking HDV spread by interfering with the initiation of productive infection of naïve hepatocytes.

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Representation of time-lines for exposure of primary hepatocytes to HDV and potential inhibitors.For the five time-lines shown the open box indicates the period of HDV exposure and the shaded box the exposure to inhibitor. The effects on HDV replication of such treatments with three different inhibitors are summarized in Table 1.
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pone-0022415-g002: Representation of time-lines for exposure of primary hepatocytes to HDV and potential inhibitors.For the five time-lines shown the open box indicates the period of HDV exposure and the shaded box the exposure to inhibitor. The effects on HDV replication of such treatments with three different inhibitors are summarized in Table 1.

Mentions: Our experimental procedure was to expose the hepatocytes to virus for only 3 h. The potential inhibitors were applied at different times relative to this. HDV RNA levels were measured 6 days post-infection, using realtime PCR. The time-lines of such treatments with virus and inhibitors are represented in Fig. 2, and the results are summarized in Table 1. It can be seen that significant inhibition was obtained when either interferon was applied during the period of virus exposure but less so after 16 h, when virus replication was initiated.


Interferon impedes an early step of hepatitis delta virus infection.

Han Z, Nogusa S, Nicolas E, Balachandran S, Taylor J - PLoS ONE (2011)

Representation of time-lines for exposure of primary hepatocytes to HDV and potential inhibitors.For the five time-lines shown the open box indicates the period of HDV exposure and the shaded box the exposure to inhibitor. The effects on HDV replication of such treatments with three different inhibitors are summarized in Table 1.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3139649&req=5

pone-0022415-g002: Representation of time-lines for exposure of primary hepatocytes to HDV and potential inhibitors.For the five time-lines shown the open box indicates the period of HDV exposure and the shaded box the exposure to inhibitor. The effects on HDV replication of such treatments with three different inhibitors are summarized in Table 1.
Mentions: Our experimental procedure was to expose the hepatocytes to virus for only 3 h. The potential inhibitors were applied at different times relative to this. HDV RNA levels were measured 6 days post-infection, using realtime PCR. The time-lines of such treatments with virus and inhibitors are represented in Fig. 2, and the results are summarized in Table 1. It can be seen that significant inhibition was obtained when either interferon was applied during the period of virus exposure but less so after 16 h, when virus replication was initiated.

Bottom Line: Similarly, this study shows that even when an interferon response was induced by transfection of poly(IC) into a cell line, HDV RNA accumulation was only modestly inhibited.These interferon treatments were shown to produce significant time-dependent increases of host response proteins such as for Stat-1, phosphoStat-1, Mx1/2/3 and PKR, and yet interferon pretreatment of hepatocytes did not confer an increased inhibition of HDV replication over interferon treatment at the time of (or after) infection.These and other data support the interpretation that interferon action against HDV replication can occur and is largely mediated at the level of entry into primary human hepatocytes.

View Article: PubMed Central - PubMed

Affiliation: Fox Chase Cancer Center, Philadelphia, Pennsylvania, United States of America.

ABSTRACT
Hepatitis delta virus (HDV) infects hepatocytes, the major cell type of the liver. Infection of the liver may be either transient or chronic. The prognosis for patients with chronic HDV infection is poor, with a high risk of cirrhosis and hepatocellular carcinoma. The best antiviral therapy is weekly administration for at least one year of high doses of interferon alpha. This efficacy of interferon therapy has been puzzling in that HDV replication in transfected cell lines is reported as insensitive to administration of interferon alpha or gamma. Similarly, this study shows that even when an interferon response was induced by transfection of poly(IC) into a cell line, HDV RNA accumulation was only modestly inhibited. However, when the HDV replication was initiated by infection of primary human hepatocytes, simultaneous addition of interferons alpha or gamma at 600 units/ml, a concentration comparable to that achieved in treated patients, the subsequent HDV RNA accumulation was inhibited by at least 80%. These interferon treatments were shown to produce significant time-dependent increases of host response proteins such as for Stat-1, phosphoStat-1, Mx1/2/3 and PKR, and yet interferon pretreatment of hepatocytes did not confer an increased inhibition of HDV replication over interferon treatment at the time of (or after) infection. These and other data support the interpretation that interferon action against HDV replication can occur and is largely mediated at the level of entry into primary human hepatocytes. Thus in vivo, the success of long-term interferon therapy for chronic HDV, may likewise involve blocking HDV spread by interfering with the initiation of productive infection of naïve hepatocytes.

Show MeSH
Related in: MedlinePlus