Abstract
BK virus (BKV) is a polyomavirus that establishes a lifelong persistence in most humans and is a major impediment to success of kidney grafts. The function of the innate immune system in BKV infection and pathology has not been investigated. Here we examine the role of antimicrobial defensins in BKV infection of Vero cells. Our data show that alpha-defensin human neutrophil protein 1 (HNP1) and human alpha-defensin 5 (HD5) inhibit BKV infection by targeting an early event in the viral lifecycle. HD5 treatment of BKV reduced viral attachment to cells, whereas cellular treatment with HD5 did not. Colocalization studies indicated that HD5 interacts directly with BKV. Ultrastructural analysis revealed HD5-induced aggregation of virions. HD5 also inhibited infection of cells by other related polyomaviruses. This is the first study to demonstrate polyomavirus sensitivity to defensins. We also show a novel mechanism whereby HD5 binds to BKV leading to aggregation of virion particles preventing normal virus binding to the cell surface and uptake into cells.
Highlights
Nephritis resulting in graft destruction and leads to transplant failure in ϳ50% of diagnosed cases [6, 7]
A robust CD8ϩ T cell response in polyomavirus-induced nephropathy (PVN) patients correlates with decreased BK virus (BKV) replication, whereas a weak CD8ϩ T cell response correlates with increased viruria and viremia [16]
Human defensins are divided into two families, ␣- and -defensins, based on the orientation of disulfide bonds. ␣-Defensins are composed of human neutrophil peptides 1– 4 (HNP1– 4), which are expressed in immune cells, and human ␣-defensin 5 (HD5)– 6, which are found in the small intestine and, described for HD5, in the urogenital tract [17,18,19,20]. -Defensins are produced by many differ
Summary
Nephritis resulting in graft destruction and leads to transplant failure in ϳ50% of diagnosed cases [6, 7]. A reduction of immunosuppressive therapy is effectively used to decrease viral replication in PVN patients suggesting that a functional immune system is critical in controlling BKV replication and pathology [11]. A robust CD8ϩ T cell response in PVN patients correlates with decreased BKV replication, whereas a weak CD8ϩ T cell response correlates with increased viruria and viremia [16]. CD4ϩ T cells play a role in modulating BKV as elevated viral replication is associated with a decreased CD4ϩ count in HIV-positive patients [15]. Together these studies indicate that cell-mediated immunity is important in controlling BKV replication and spread in the human host. We reveal that two ␣-defensins, HNP1 and HD5, significantly inhibit BKV infection and propose a novel mechanism by which these peptides inhibit viral infection
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