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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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Time-dependent induction by interferons alpha and gamma of innate immune response proteins in primary hepatocytes.Hepatocytes were exposed to either interferons alpha or gamma at 600 units/ml. At time points out to 24 h, as indicated, total cell protein was extracted and analyzed by immunoblot to detect the indicated host proteins. Note that after 2 hours of treatment with interferon gamma, the pSTAT1 increases but not the total STAT1; this is because only a small fraction of the total STAT1 undergoes phosphorylation.
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pone-0022415-g003: Time-dependent induction by interferons alpha and gamma of innate immune response proteins in primary hepatocytes.Hepatocytes were exposed to either interferons alpha or gamma at 600 units/ml. At time points out to 24 h, as indicated, total cell protein was extracted and analyzed by immunoblot to detect the indicated host proteins. Note that after 2 hours of treatment with interferon gamma, the pSTAT1 increases but not the total STAT1; this is because only a small fraction of the total STAT1 undergoes phosphorylation.

Mentions: Interferon treatments can induce an innate response but this outcome can be host cell specific [21], [22]. Therefore, it was obligatory to test whether that our experimental conditions induced such a response in the cultured primary human hepatocytes. Using immunoblot assays we found, as shown in Fig. 3, that both interferons at 600 units/ml induced time-dependent changes of known host innate response proteins in the primary hepatocytes. Increases were seen for Stat 1, pStat 1, Mx-1/2/3 and PKR. Interferon alpha had more effect than interferon gamma. As expected no changes were detected for beta-actin.


Interferon impedes an early step of hepatitis delta virus infection.

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

Time-dependent induction by interferons alpha and gamma of innate immune response proteins in primary hepatocytes.Hepatocytes were exposed to either interferons alpha or gamma at 600 units/ml. At time points out to 24 h, as indicated, total cell protein was extracted and analyzed by immunoblot to detect the indicated host proteins. Note that after 2 hours of treatment with interferon gamma, the pSTAT1 increases but not the total STAT1; this is because only a small fraction of the total STAT1 undergoes phosphorylation.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0022415-g003: Time-dependent induction by interferons alpha and gamma of innate immune response proteins in primary hepatocytes.Hepatocytes were exposed to either interferons alpha or gamma at 600 units/ml. At time points out to 24 h, as indicated, total cell protein was extracted and analyzed by immunoblot to detect the indicated host proteins. Note that after 2 hours of treatment with interferon gamma, the pSTAT1 increases but not the total STAT1; this is because only a small fraction of the total STAT1 undergoes phosphorylation.
Mentions: Interferon treatments can induce an innate response but this outcome can be host cell specific [21], [22]. Therefore, it was obligatory to test whether that our experimental conditions induced such a response in the cultured primary human hepatocytes. Using immunoblot assays we found, as shown in Fig. 3, that both interferons at 600 units/ml induced time-dependent changes of known host innate response proteins in the primary hepatocytes. Increases were seen for Stat 1, pStat 1, Mx-1/2/3 and PKR. Interferon alpha had more effect than interferon gamma. As expected no changes were detected for beta-actin.

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