Human Serum Facilitates Hepatitis C Virus Infection, and Neutralizing Responses Inversely Correlate with Viral Replication Kinetics at the Acute Phase of Hepatitis C Virus Infection

Abstract

The factors leading to spontaneous clearance of hepatitis C virus (HCV) or to viral persistence are elusive. Understanding virus-host interactions that enable acute HCV clearance is key to the development of more effective therapeutic and prophylactic strategies. Here, using a sensitive neutralization assay based on infectious HCV pseudoparticles (HCVpp), we have studied the kinetics of humoral responses in a cohort of acute-phase patients infected during a single nosocomial outbreak in a hemodialysis center. The 17 patients were monitored for the spontaneous outcome of HCV infection for 6 months before a treatment decision was made. Blood samples were taken frequently (15 ؎ 4 per patient). Phylogenetic analysis of the predominant virus(es) revealed infection by only one of two genotype 1b strains. While all patients seroconverted, their sera induced two opposing effects in HCVpp infection assays: inhibition and facilitation. Furthermore, the ability of sera to facilitate or inhibit infection correlated with the presence of either infecting HCV strain and divided the patients into two groups. In group 1, the progressive emergence of a relatively strong neutralizing response correlated with a fluctuating decrease in high initial viremia, leading to control of viral replication. Patients in group 2 failed to reduce viremia within the acute phase, and no neutralizing responses were detected despite seroconversion. Strikingly, sera of group 2, as well as naïve sera, facilitated infection by HCVpp displaying HCV glycoproteins from different genotypes and strains, including those retrieved from patients. These results provide new insights into the mechanisms of viral persistence and immune control of viremia.Hepatitis C virus (HCV) infection causes acute hepatitis after 4 to 12 weeks of incubation. Acute hepatitis is characterized by elevated alanine aminotransferase (ALT) levels, with generally no or only mild symptoms. Among infected individuals, only 20% clear infection spontaneously, whereas ϳ80% progress to chronic infection. Chronic hepatitis may lead after 10 to 30 years to severe, life-threatening complications, such as cirrhosis and hepatocellular carcinoma. With an estimated 170 million people infected, i.e., nearly 3% of the world population, and an incidence of ϳ3 to 4 million new infections per year, HCV is presently a leading cause of chronic liver disease and poses a major public health problem. In the United States, HCV constitutes the most common chronic blood-borne infectious disease and is the principal indication for liver transplantation and the 10th leading cause of deaths among adults. The only approved therapy for chronic hepatitis C is the combination of alpha interferon, used in a pegylated form, and ribavirin. This treatment cures infection in a significant proportion of patients, but its efficacy against HCV genotype 1, the most frequent HCV genotype in industrialized countries, remains limited, and it can cause significant side effects (18,23,36). HCV is a highly variable virus that compri...

Immune protection against reinfection with nonprimate hepacivirus

“…In addition, the role of virus-specific antibodies needs to be further addressed. In humans, HCV strain-specific neutralizing antibodies have been found to be associated with spontaneous recovery (43,44). Our reinfected horses displayed a higher titer of NPHV-specific antibodies before rechallenge, which even further increased after a new exposure.…”

Oxidized low-density lipoprotein inhibits hepatitis C virus cell entry in human hepatoma cells

“…39,40 SR-BI was initially reported as a candidate receptor for HCV because of its ability to bind to sE2. 14 Subsequent reports have shown that antibodies and siRNA targeting SR-BI inhibit HCVpp entry 15,17,41 (Fig. 4).…”

A milestone for hepatitis C virus research: A virus generated in cell culture is fully viable in vivo

“…This finding raises the possibility that specific proteins released by human or chimpanzee hepatocytes enhance infectivity of HCV. This phenomenon has recently been observed in the HCV pseudovirus system, in which the entry of retroviral pseudovirus particles bearing the envelope proteins of HCV was found to be enhanced by serum from chimpanzees and humans, human lipoproteins, and human apolipoproteins (20)(21)(22)(23). Thus, it is a possibility that such lipoproteins and apolipoproteins might also enhance the infectivity of HCV in cell culture.…”