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Chapter 54 : Hepatitis C Virus

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Abstract:

Hepatitis C virus (HCV), a member of the genus in the family (1), is a single-stranded RNA virus that infects humans and other higher primates, and has a selective tropism to the liver. Following exposure, HCV is able to evade the host's immune system and establish a chronic, often asymptomatic, infection that may lead to liver failure, hepatocellular carcinoma, and death. Transmitted primarily by exposure to infected blood, but also through sexual and perinatal routes, the virus is estimated to infect 2.8% of the world's population (2). Originally termed non-A, non-B hepatitis, infection with HCV was a frequent cause of transfusion-related hepatitis until discovery of the virus in 1989 (3, 4) and the subsequent development of effective screening methods. Many substantial advances have recently been made in treating HCV infection, and it is now possible to cure over 90% of patients with HCV infection. These advances also provide promising opportunities for future public health efforts to effectively reduce the disease burden of this global infection.

Citation: Koh C, Li Q, Liang J. 2017. Hepatitis C Virus, p 1313-1345. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch54
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Image of FIGURE 1
FIGURE 1

Phylogenetic tree of 129 representative complete coding region sequences demonstrating clustering to 7 genotypes and 67 subtypes. For genotypes 1, 2, 3, 4, and 6, the lowest common branch shared by all subtypes and supported by 100% of bootstrap replicates (n = 1,000) is indicated by ·. (Reprinted from Smith et al. ( ) with permission.)

Citation: Koh C, Li Q, Liang J. 2017. Hepatitis C Virus, p 1313-1345. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch54
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Image of FIGURE 2
FIGURE 2

Geographic distribution of HCV genotypes. Genotype 1 is the most prevalent and can be seen worldwide. Genotype 3 is more common in South- and South-East Asia, genotype 4 is seen almost exclusively in patients from Central Africa, Egypt and Saudi Arabia, genotype 5 is mostly confined to South Africa, and genotype 6 to South-East Asia.

Citation: Koh C, Li Q, Liang J. 2017. Hepatitis C Virus, p 1313-1345. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch54
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Image of FIGURE 3
FIGURE 3

Electron microscopy of viral particles. (a) Immunogold electron microscopy of a viral particle from patient serum. The sample was incubated with Anti E1 polyclonal antibody and a secondary antibody conjugated to colloidal gold particles. An inner core (arrow) seems to be included within the particle. Reprinted from Kaito et al. ( ) with permission. (b) Negative stain electron microscopy of HCV harvested from Huh-7.5 cells infected with HCV strain JFH-1. Spherical particles of uniform size with inner cores can be seen.

Citation: Koh C, Li Q, Liang J. 2017. Hepatitis C Virus, p 1313-1345. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch54
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Image of FIGURE 4
FIGURE 4

Genome structure of HCV. (a) The positive-sense single-strand RNA genome of HCV has one long open reading frame, containing genes for 3 structural and 7 nonstructural proteins, and flanked by two untranslated regions. (b) Sequence and secondary structure of the 5′ UTR. The AUG start-codon for the open reading frame is highlighted in stem-loop IV. (c) Sequence and secondary structure of the 3′ UTR region. Arrows indicate variable base pairs in the stem of SL1 and the asterisk denotes the variable nucleotide in the loop of SL1. UTR—untranslated region.

Citation: Koh C, Li Q, Liang J. 2017. Hepatitis C Virus, p 1313-1345. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch54
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Image of FIGURE 5
FIGURE 5

Viral replication cycle. Binding of the virus to the cell surface and internalization are followed by release of the viral RNA, harnessing of the cellular ribosomes, and protein translation and processing. The viral proteins, associated with the ER membrane, promote the formation of replication complexes anchored to lipid membranous webs in which the RNA dependent polymerase NS5B creates copies of the viral RNA through a negative strand RNA intermediate. HCV RNA is then packaged into membrane-covered viral particles and exported from the cell, presumably through the exocytosis pathway.

Citation: Koh C, Li Q, Liang J. 2017. Hepatitis C Virus, p 1313-1345. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch54
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Image of FIGURE 6
FIGURE 6

World distribution of HCV seroprevalence. The highest prevalence is in Egypt. Other countries with high prevalence of infection include Mongolia, Bolivia, and several sub-Saharan nations.

Citation: Koh C, Li Q, Liang J. 2017. Hepatitis C Virus, p 1313-1345. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch54
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Image of FIGURE 7
FIGURE 7

The evolution of screening methods for donated blood and the corresponding decrease in transfusion-related hepatitis. Data shown for non-A, non-B hepatitis before the availability of anti-HCV testing, and for HCV afterwards. HBsAg—hepatitis B virus surface antigen. Anti-HBc—hepatitis B virus core antibodies. NAT—nucleic acid technology. (Adapted from reference .)

Citation: Koh C, Li Q, Liang J. 2017. Hepatitis C Virus, p 1313-1345. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch54
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Image of FIGURE 8
FIGURE 8

Histopathologic findings in chronic hepatitis C. (a) Moderate inflammatory activity. The portal area is expanded by an inflammatory infiltrate and a lymphoid follicle (arrow). The infiltrate disrupts the limiting plate between portal area and hepatic parenchyma (“interface hepatitis”, arrowheads). Foci of lobular inflammation can also be seen (white arrowhead) as well as an acidophil body (white arrow). H&E stain, 400× magnification. (b) HCV-associated steatosis. The inflammatory infiltrate (arrow) is accompanied by fat droplets in hepatocytes (arrowheads). H&E stain, 200× magnification. Images provided by David Kleiner, MD PhD, National Cancer Institute, Bethesda, MD.

Citation: Koh C, Li Q, Liang J. 2017. Hepatitis C Virus, p 1313-1345. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch54
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Image of FIGURE 9
FIGURE 9

The immune response to HCV infection. Hepatitis C infection induces innate and adaptive immune responses. Induction of HCV-specific cytotoxic T-cells by antigen presenting cells is crucial in viral clearance and prevention of chronic infection, through both cytopathic and noncytopathic mechanisms. Antibodies against HCV, secreted by B-cells, appear late and do not seem to have an important role in viral control. Activation of nonspecific inflammatory cells causes liver injury. Chronic stimulation of lymphoid cells can induce autoimmunity and lymphoproliferative disorders including cryoglobulinemia and lymphoma.

Citation: Koh C, Li Q, Liang J. 2017. Hepatitis C Virus, p 1313-1345. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch54
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Image of FIGURE 10
FIGURE 10

The clinical course and natural history of HCV infection. (a) Acute, spontaneously resolving hepatitis C. The liver enzyme elevation, symptoms, and appearance of antibodies usually lag behind viremia. Seropositivity persists for years after recovery but may decline after decades. (b) Acute infection progressing to chronic hepatitis C. Viral levels and enzyme elevations are relatively stable in the chronic phase. Accumulation of fibrosis occurs gradually, over many years. The gray dashed line represents the upper limit of the norm for ALT. HCVAb—anti-HCV antibodies. ALT—alanine aminotransferase.

Citation: Koh C, Li Q, Liang J. 2017. Hepatitis C Virus, p 1313-1345. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch54
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Image of FIGURE 11
FIGURE 11

The evolution of treatment regimens for chronic hepatitis C and the corresponding rates of sustained virological response. IFN—interferon alfa. PIFN—pegylated interferon alfa. R—ribavirin. DAA—direct-acting antiviral therapy.

Citation: Koh C, Li Q, Liang J. 2017. Hepatitis C Virus, p 1313-1345. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch54
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Image of FIGURE 12
FIGURE 12

Currently FDA approved direct-acting antiviral therapy for hepatitis C includes NS3-4A protease inhibitors, nucleotide analogue, and non-nucleoside inhibitors of the HCV RNA-dependent RNA polymerase (RdRp) and inhibitors of the non-structural 5A (NS5A) protein.

Citation: Koh C, Li Q, Liang J. 2017. Hepatitis C Virus, p 1313-1345. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Fourth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555819439.ch54
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