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Identification of novel human kinases that suppress hepatitis C virus infection.

ABSTRACT: The human kinome includes between 500 and 600 known kinases and open reading frames (ORFs) that play key roles in regulating many cellular processes. Past studies adopting loss-of-function approaches have identified some kinases whose activities are required for hepatitis C virus (HCV) life cycle. Here, by screening a retroviral cDNA library of 192 active human kinases, we found that three of them, namely cyclin-dependent kinases regulatory subunit 1 (CKS1B), mitogen-activated protein kinase kinase 5 (MAP2K5) and protein kinase C and casein kinase substrate in neurons 1 (PACSIN1), potently suppressed HCV infection. The expression of these kinases did not induce the production of type I interferon (IFN) and interferon-stimulated genes (ISGs); instead, they inhibited HCV at postentry stages. Specifically, CKS1B and MAP2K5 significantly inhibited viral RNA replication. PACSIN1, by contrast, inhibited HCV infection by decreasing the level of HCV p7. Altogether, the identification of human protein kinases that exert an anti-HCV activity highlighted the potential of combating HCV infection by activating specific kinase-mediated pathways, offering an alternative strategy of treatment.

SUBMITTER: Lee A

PROVIDER: S-EPMC4130908 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Hepatitis C virus (HCV) and human pegivirus (HPgV), formerly GBV-C, are the only known human viruses in the Hepacivirus and Pegivirus genera, respectively, of the family Flaviviridae. We present the discovery of a second pegivirus, provisionally designated human pegivirus 2 (HPgV-2), by next-generation sequencing of plasma from an HCV-infected patient with multiple bloodborne exposures who died from sepsis of unknown etiology. HPgV-2 is highly divergent, situated on a deep phylogenetic branch in a clade that includes rodent and bat pegiviruses, with which it shares <32% amino acid identity. Molecular and serological tools were developed and validated for high-throughput screening of plasma samples, and a panel of 3 independent serological markers strongly correlated antibody responses with viral RNA positivity (99.9% negative predictive value). Discovery of 11 additional RNA-positive samples from a total of 2440 screened (0.45%) revealed 93-94% nucleotide identity between HPgV-2 strains. All 12 HPgV-2 RNA-positive cases were identified in individuals also testing positive for HCV RNA (12 of 983; 1.22%), including 2 samples co-infected with HIV, but HPgV-2 RNA was not detected in non-HCV-infected individuals (p<0.0001), including those singly infected by HIV (p = 0.0075) or HBV (p = 0.0077), nor in volunteer blood donors (p = 0.0082). Nine of the 12 (75%) HPgV-2 RNA positive samples were reactive for antibodies to viral serologic markers, whereas only 28 of 2,429 (1.15%) HPgV-2 RNA negative samples were seropositive. Longitudinal sampling in two individuals revealed that active HPgV-2 infection can persist in blood for at least 7 weeks, despite the presence of virus-specific antibodies. One individual harboring both HPgV-2 and HCV RNA was found to be seronegative for both viruses, suggesting a high likelihood of simultaneous acquisition of HCV and HPgV-2 infection from an acute co-transmission event. Taken together, our results indicate that HPgV-2 is a novel bloodborne infectious virus of humans and likely transmitted via the parenteral route.

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Identification of novel human kinases that suppress hepatitis C virus infection.

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