Activation and utilization of these proteins upon initiation of viral infection are therefore required for productive infection and resultant viral disease. IMPORTANCE Viruses usurp cellular factors to invade host cells. These conclusions illuminate key host factors that regulate clathrin-mediated endocytosis of JCPyV, which is necessary for viral internalization and productive infection. Furthermore, mutagenesis of a β-arrestin binding domain (Ala-Ser-Lys) within the intracellular C terminus of 5-HT 2AR severely diminished internalization and infection, suggesting that β-arrestin interactions with 5-HT 2AR are critical for JCPyV infection and entry.
Inhibition of clathrin or β-arrestin specifically reduced JCPyV internalization but did not affect viral attachment. However, infectivity of the polyomavirus simian virus 40 (SV40) was not affected by CME-specific treatments. Treatment of cells with small-molecule chemical inhibitors and RNA interference of 5-HT 2R endocytic machinery, including β-arrestin, clathrin, AP2, and dynamin, significantly reduced JCPyV infection. However, the JCPyV entry process and the cellular factors involved in viral internalization remain poorly understood. JCPyV internalization is dependent on serotonin 5-hydroxytryptamine subfamily 2 receptors (5-HT 2Rs), and entry is thought to occur by clathrin-mediated endocytosis (CME). Initiation of infection is mediated through viral attachment to α2,6-sialic acid-containing lactoseries tetrasaccharide c (LSTc) on the surface of host cells. Under conditions of severe immunosuppression or immune modulation, JCPyV can reactivate in the central nervous system (CNS) and cause progressive multifocal leukoencephalopathy (PML), a fatal demyelinating disease. JC polyomavirus (JCPyV) establishes a persistent, lifelong, asymptomatic infection within the kidney of the majority of the human population.
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