Occult Hepatitis C Virus Infection and Its Relevance in Clinical Practice

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Hepatitis C virus (HCV) can persist in the liver, lymphoid (immune) cells, and serum of individuals long after an apparently complete therapy-induced or a spontaneous resolution of hepatitis C. This essential asymptomatic infection, called secondary occult HCV infection (OCI), usually occurs in anti-HCV antibody reactive individuals with normal liver function tests. This infection has been identified when the nucleic acid amplification assays of enhanced sensitivity were applied for the detection of HCV genome and its replication. In addition to the secondary OCI, a form of low-level HCV-RNA-positive infection of unknown etiology coinciding with moderately elevated serum liver enzymes and progressing in the absence of anti-HCV detectable by standard clinical assays has been reported. Because of its undefined origin, it can be termed cryptogenic OCI. In this review, the general characteristics of OCI, the ways of its detection and associated controversies, and the potential clinical implications of its existence will be concisely outlined.

Hepatitis C virus (HCV) is a human blood-borne pathogen responsible for over 170 million chronic infections worldwide. At least 35% of the infected individuals with a symptomatic acute infection spontaneously resolve hepatitis, while the rest develop chronic hepatitis C (CHC) and persistently carry virus at levels normally detectable by clinical laboratory tests. Chronic HCV infection can lead to liver fibrosis, cirrhosis, liver failure, and hepatocellular carcinoma (HCC), and end-stage liver disease caused by HCV is the leading cause of liver transplantation in many parts of the world.

The HCV is a highly heterogeneous, single-stranded ribonucleic acid (RNA) virus with at least six major genotypes (designated as 1, 2, 3, etc.), many subtypes (designated as a, b, c, etc.), and uncountable variants. The virus propagatesby making a complementary RNA negative strand. Although traditionally thought to infect primarily hepatocytes, HCV has also been shown in different studies to invade and replicate in other cell types, such as those of the immune system.2 In the in vivo setting, T and B lymphocytes, monocytes, and dendritic cells from patients with hepatitis C have been reported to carry HCV-RNA positive and, in many instances, HCV-RNA negative (replicative) strand.3€"6 Further, the culture supernatant from ex vivo stimulated lymphoid cells from some of these patients has been shown to contain infectious HCV capable of inducing de novo infection of primary T cells.7,8 Similarly, in the context of in vitro cell culture models, primary T cells and monocytes/macrophages, as well as various T and B cell lines, have been shown to be able to support productive HCV replication, although to a highly variable degree and usually at very low levels.7,9,10 The latter is evidenced by the detection of HCV-RNA negative strand, synthesis of viral proteins, emergence of immune cellassociated viral variants, release of infectious HCV-like virus particles, susceptibility of virus in infected cells to anti-viral treatment, and altering host's immune responses.7,9
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