Distribution of markers of hepatitis C virus infection throughout the body.

The detection of markers of hepatitis C virus (HCV) infection is complicated by the presence of virus in circulating blood. Consequently, it is necessary to target the negative-strand virus RNA or the nonstructural proteins. This has proved challenging, due to unforeseen difficulties in the specific detection of negative-strand viral RNA. However, recent data suggest that although the liver is the major target organ, the virus may be able to replicate in peripheral blood mononuclear cells, lymph nodes, and pancreas and to a more limited degree in bone marrow cells, thyroid, adrenal glands, and spleen. An analysis of the distribution of virus-infected cells in the liver has proved equally challenging. It is clear from the paucity of data generated by immunoblot and Northern blot hybridization that the level of HCV replication in the liver is very low, and this has necessitated studies to detect the viral RNA and antigens by in situ hybridization and immunohistochemistry, respectively. The results of these studies are quite disparate. Those related to in situ hybridization are nonreproducible and reflect wide disparities in the methodology used by different research workers. The data are often internally inconsistent or are inconsistent with data generated by nucleic acid amplification methods to detect the viral RNA in purified RNA extracts or inconsistent with our current understanding of the virus replication cycle. In contrast, the detection of the viral proteins is more reproducible, and some consensus can be reached. It is clear that frozen sections rather than formalin-fixed paraffin-embedded tissue are preferable. Indeed, it is likely that the use of the latter samples can generate nonspecific positive reactions. Surprisingly, many of the most useful data were derived by the use of polyclonal human antibodies from chronic carriers. HCV proteins were detected in the cytoplasm of infected hepatocytes, often in a punctate granular pattern in some hepatocytes and occasionally in monocytes and other cell types. There is often no correlation between HCV antigen expression and the degree of liver cell injury, although patients with lower levels of antigen expression are more likely to respond to interferon therapy.