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Human parechovirus 1 (HPEV-1) is a prototype member of parechoviruses, a recently established picornavirus genus. Although there is preliminary evidence that HPEV-1 recognizes ␣ V integrins as cellular receptors, our understanding of early events during HPEV-1 infection is still very limited. The aim of this study was to clarify the entry mechanisms of HPEV-1, including the attachment of the virus onto the host cell surface and subsequent internalization. In blocking experiments with monoclonal antibodies against different receptor candidates, antibodies against ␣ V and ␤ 3 integrin subunits, in particular in combination, appeared to be the most efficient ones in preventing the HPEV-1 infection. To find out whether HPEV-1 uses clathrin-coated vesicles or other routes for the entry into the host cell, we carried out double-labeling experiments of virus-infected cells with anti-HPEV-1 antibodies and antibodies against known markers of the clathrin and the caveolin routes. At the early phase of infection (5 min postinfection [p.i.]) HPEV-1 colocalized with EEA1 (early endosomes), and later, after 30 min p.i., it colocalized with mannose-6-phosphate receptor (late endosomes), whereas no colocalization with caveolin-1 was observed. The data indicate that HPEV-1 utilizes the clathrin-dependent endocytic pathway for entry into the host cells. Interestingly, endocytosed HPEV-1 capsid proteins were observed in the endoplasmic reticulum and cis-Golgi network 30 to 60 min p.i. Depolymerization of microtubules with nocodazole inhibited translocation of the virus to the late endosomes but did not block HPEV-1 replication, suggesting that the RNA genome may be released early during the entry process.Early events in viral infection include specific attachment of the virion onto the cell surface receptor(s) followed by entry into the cell and subsequent release of the genome. Successful completion of this process is a prerequisite for the initiation of the infection cycle, and these events play an important role in tissue tropism and pathogenesis. Recently, numerous cell surface molecules, with wide variation in their structures and normal physiological functions, have been identified as virus receptors.The routes by which extracellular ligands, including viruses, are internalized into the cell include clathrin-mediated endocytosis, uptake via caveolae, macropinocytosis, phagocytosis, and other pathways that presently are poorly characterized. For some virus systems, the entry events have been described in detail. For instance, both adenovirus type 2, a nonenveloped DNA virus, and Semliki Forest virus, an enveloped RNA virus, enter the host cells through a clathrin-mediated pathway (7,8,19,39,42). Different members of the polyomavirus family are known to enter the host cell by distinct mechanisms; simian virus 40 uses the caveola-dependent endocytic route, while the human polyomavirus JC virus enters the cells through clathrinmediated endocytosis (24, 32).Picornaviruses include several important human pathogens which belong to ...

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Parechoviruses are a recently established group of human viral pathogens. At the time of their first isolation, parechoviruses were classified among the enterovirus genus in the picornavirus family, but based on their different biological properties they were separated into their own genus. The type member is human parechovirus 1 (HPEV1), which frequently infects humans, in particular small children. The parechovirus genus also includes HPEV2 and the Ljungan virus, which was recently isolated from rodents, is a candidate for the group. Seroepidemiological studies have shown that the prevalence of HPEV1 antibodies is surprisingly high, exceeding 95% in adult populations. According to present data, HPEV1 causes mainly gastrointestinal and respiratory infections; however, severe disease conditions, such as myocarditis and encephalitis, have also been reported. HPEV2 infections appear to be rare, and it is currently not known whether the Ljungan virus can infect humans.