Immunopathogenesis of chronic hepatitis C virus infection.

It is estimated that there are more than 170 million persons infected with the hepatitis C virus (HCV) worldwide (1,2). Approximately 4 million individuals in the United States, or 1.8% of the general population, show evidence of having been infected with HCV (3). The majority of those are persistently viremic (approximately 2.7 million). In the United States, the prevalence of HCV in children is 0.2% (under 12 years) to 0.4% (12 to 19 years) (3). Since blood-donor screening was initiated in 1990, HCV is rarely transmitted by blood transfusion in developed countries (4). Injection drug use currently accounts for most HCV transmission in adults in USA. Following acute infection with HCV, about 10 to 50% of adult patients will clear the virus and the remaining patients will develop chronic infection (5). According to older published reports on children, which generally describe children referred to university centers in the past, children acquired HCV principally through the transfusion of blood or blood products or through perinatal transmission (6). The rate of motherto-infant transmission of HCV is approximately 4 to 5% (6,7) but is higher when the mother is co-infected with HIV (8,9). In a recent study of HCV in children who presumably acquired HCV from neonatal blood transfusions and who were then followed for about 20 years, 55% of the anti-HCV-positive patients had detectable HCV RNA in their blood at the time of reevaluation, suggesting a higher rate of spontaneous viral clearance than in adult patients (10). This study also demonstrated that the clinical manifestations of hepatitis C in the infected children were minimal. The reasons for the apparent differences in viral clearance between adults and children are not clear but different host immune response in children may be implicated. Unfortunately, there are no data available to date which demonstrate that infants do indeed mount a better immunologic response to HCV than adults. A recent report of Conte et al. (7) showed that 18 newborns born to HCV-infected mothers had detectable HCV-RNA in cord blood samples, 16 of whom became HCV-RNA-negative at 4 months of age. The authors attributed the HCV-RNA-positivity in the cord blood samples to maternal blood contamination. On the other hand, this same study may imply that infants were able to mount vigorous immune responses against HCV. The hepatitis C virus (HCV) has been classified as a member of the Flaviviridae family (11). It is an enveloped positive-stranded RNA virus of approximately 9.6 kb, which consists of a 5 non-translated region (NTR), a single uninterrupted open reading frame (ORF) encoding the viral polyprotein and a 3 NTR. The polyprotein encoded by the HCV ORF includes the capsid or core protein C, the envelope glycoprotein E1 and E2, a small polypeptide of unknown function known as p7, and six nonstructural (NS) proteins: NS2, NS3, NS4A, NS4B, NS5A, and NS5B (12). The nucleocapsid (core) protein has the highest sequence homology among all isolates sequenced to date. E1 and E2 form non-covalent heterodimers, which are believed to represent the functional subunit embedded in the lipid envelope of the virion. Comparison of the HCV sequences has shown two hypervariable regions within E2, called HVR1 (amino acids 390–410) and HVR 2 (amino acids 474–480) (13). Mutations in HVR 1 occur during the course of HCV infection in individual patients and may be involved in HCV escape from antiviral immune response. It is believed that HCV is not cytopathic for infected cells. Therefore, immune responses must play a central role in the pathogenesis of HCV (14). Extensive research has been focused on the nature of the immune response and the cytokine profile in HCV infection. Much has been learned in the past few years about the mechanism for HCV clearance and persistence. Specifically, a strong T helper type 1 (Th1) response against viral antigens such as NS3 and a robust CD8+ cytotoxic T-cell (CTL) Address correspondence and requests for reprints to Kathleen B. Schwarz, MD, 600 N. Wolfe Street, Brady 320, Division of Pediatric Gastroenterology and Nutrition, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, U.S.A. (e-mail: kschwarz@ jhmi.edu).