Clinical and Therapeutic Implications of Hepatitis C Virus Compartmentalization

Liberto, Gaëtana Di; Roque–Afonso, Anne–Marie; Kara, Rachid; Ducoulombier, Delphine; Fallot, Guillaume; Samuel, Didier; Féray, Cyrille

doi:10.1053/j.gastro.2006.04.016

Cited by 86 publications

(86 citation statements)

References 35 publications

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“…The combination of receptors and expression rates in hepatocytes is one element that explains why the liver constitutes the main target for HCV particles. However, many studies have shown that HCV may also infect peripheral blood mononuclear cells (PBMCs) (10)(11)(12)(13)(14)(15)(16)(17). Indeed, the presence of positive or negative HCV RNA as well as structural or nonstructural viral proteins has been characterized in PBMCs of chronically HCV-infected patients or in perihepatic lymph nodes (12)(13)(14)(15)(16)18).…”

mentioning

confidence: 99%

Specialization of Hepatitis C Virus Envelope Glycoproteins for B Lymphocytes in Chronically Infected Patients

Douam

Bobay

Maurin

et al. 2016

J Virol

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Hepatitis C virus (HCV) productively infects hepatocytes. Virion surface glycoproteins E1 and E2 play a major role in this restricted cell tropism by mediating virus entry into particular cell types. However, several pieces of evidence have suggested the ability of patientderived HCV particles to infect peripheral blood mononuclear cells. The viral determinants and mechanisms mediating such events remain poorly understood. Here, we aimed at isolating viral determinants of HCV entry into B lymphocytes. For this purpose, we constructed a library of full E1E2 sequences isolated from serum and B lymphocytes of four chronically infected patients. We observed a strong phylogenetic compartmentalization of E1E2 sequences isolated from B lymphocytes in one patient, indicating that E1E2 glycoproteins can represent important mediators of the strong segregation of two specialized populations in some patients. Most of the E1E2 envelope glycoproteins were functional and allowed transduction of hepatocyte cell lines using HCV-derived pseudoparticles. Strikingly, introduction of envelope glycoproteins isolated from B lymphocytes into the HCV JFH-1 replicating virus switched the entry tropism of this nonlymphotropic virus from hepatotropism to lymphotropism. Significant detection of viral RNA and viral proteins within B cells was restricted to infections with JFH-1 harboring E1E2 from lymphocytes and depended on an endocytic, pH-dependent entry pathway. Here, we achieved for the first time the isolation of HCV viral proteins carrying entry-related lymphotropism determinants. The identification of genetic determinants within E1E2 represents a first step for a better understanding of the complex relationship between HCV infection, viral persistence, and extrahepatic disorders. IMPORTANCEHepatitis C virus (HCV) mainly replicates within the liver. However, it has been shown that patient-derived HCV particles can slightly infect lymphocytes in vitro and in vivo, highlighting the existence of lymphotropism determinants within HCV viral proteins. We isolated HCV envelope glycoproteins from patient B lymphocytes that conferred to a nonlymphotropic HCV the ability to enter B cells, thus providing a platform for characterization of HCV entry into lymphocytes. This unusual tropism was accompanied by a loss of entry function into hepatocytes, suggesting that HCV lymphotropic variants likely constitute a distinct but parallel source for viral persistence and immune escape within chronically infected patients. Moreover, the level of genetic divergence of B-cell-derived envelopes correlated with their degree of lymphotropism, underlining a long-term specialization of some viral populations for B-lymphocytes. Consequently, the clearance of both hepatotropic and nonhepatotropic HCV populations may be important for effective treatment of chronically infected patients.

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confidence: 99%

Specialization of Hepatitis C Virus Envelope Glycoproteins for B Lymphocytes in Chronically Infected Patients

Douam

Bobay

Maurin

et al. 2016

J Virol

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“…In fact, sequences of HCV, although it is considered a hepatotropic virus, can be detected in PBMC, central nervous system and liver biopsy, as reported by several studies (17)(18)(19).…”

Section: Discussionmentioning

confidence: 67%

Diagnostic and Therapeutic Implications in a Case of Mixed Hepatitis C Virus (HCV) Infection

Bruzzone

Leo²,

Sticchi

et al. 2017

Hepat Mon

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Introduction: Hepatitis C virus (HCV) multiple infections can influence the course of the disease, either by boosting hepatocellular injury or by increasing the frequency of exacerbations. Their prevalence ranges from 5% to 39% in individuals with HCV infection, with a higher impact on injection drug users (IDUs), or in prison settings. Case Presentation: The current paper reported a case of dual HCV infection in a 31-year-old female, with a referred vertical transmission of HCV infection and also a history of IDU, who harbored a subtype 4d since youth. Treatment failure, after a 24-week course of sofosbuvir/ledipasvir, prompted a reevaluation of present and past HCV status. HCV genotype was determined by INNO-LiPA TM HCV II kit (LiPA II) (Innogenetics, Ghent, Belgium) and sequencing of NS5B region (nucleotide 8281 -8679). Direct-acting antivirals (DAAs) resistance profile was investigated by NS3/4, NS5A and NS5B sequencing with specific primers. The Sentosa® SQ next generation sequencing (NGS) workflow was further performed in the baseline and failure samples. Unexpectedly, a subtype 4d in the pretreatment sample and a subtype 1a in the posttreatment were identified. No resistance associated mutations (RAS) were detected in the subtype 4d, although the 170AV and 174S in the NS3/4 gene, the 30R in the NS5A gene, and the 444D in the NS5B gene were detected in the subtype 1a virus from the failure sample. Conclusions: Two main hypotheses were raised: a reinfection with a new subtype 1a virus during the treatment with a wild type strain, which developed RAS after infection or with an already mutated virus; and a pretreatment hidden dual subtype 4d plus 1a infection.

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“…While the possibility of infection with multiple genotypes presenting a multiple quasispecies variants can not be excluded, mixed genotype infections appear to be rare. 67,68 An alternate explanation for HCV quasispecies changes is that they are directly related to IDU itself and such a possibility is supported by a reported association between active IDU and increased diversity in the HIV env region. 69 HIV superinfection is unlikely to affect HIV quasispecies dynamics among IDUs, as it is a relatively rare event.…”

Section: Discussionmentioning

confidence: 99%

Hepatitis C virus quasispecies in HIV-infected women: Role of injecting drug use and highly active antiretroviral therapy (HAART)

et al. 2007

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Clinical and Therapeutic Implications of Hepatitis C Virus Compartmentalization

Cited by 86 publications

References 35 publications

Specialization of Hepatitis C Virus Envelope Glycoproteins for B Lymphocytes in Chronically Infected Patients

Specialization of Hepatitis C Virus Envelope Glycoproteins for B Lymphocytes in Chronically Infected Patients

Diagnostic and Therapeutic Implications in a Case of Mixed Hepatitis C Virus (HCV) Infection

Hepatitis C virus quasispecies in HIV-infected women: Role of injecting drug use and highly active antiretroviral therapy (HAART)

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