Adenovirus type 5 fiber knob binds to MHC class I α2 domain at the surface of human epithelial and B lymphoblastoid cells

Abstract

Adenovirus serotype 5 (Ad5) fiber receptor was investigated using reverse antibody biopanning of a phage‐displayed hexapeptide library, and virus‐neutralizing monoclonal antibodies (mAbs 1D6.3 and 7A2.7) raised against recombinant Ad5 fiber knob. Both mAbs inhibited attachment of Ad5 to HeLa cells. Mimotopes of 1D6.3 showed homology with the C‐terminal segment of the α2 domain of the heavy chain of human MHC class I molecules (MHC‐I α2), and mimotopes of 7A2.7 were consensus to human fibronectin type III (FNIII) modules. In vitro, GST‐fused MHC‐I α2‐ and FNIII‐derived oligopeptides interacted with recombinant fibers in a subgroup‐specific manner. In vivo, the MHC–I α2 synthetic icosapeptide RAIVGFRVQWLRRYFVNGSR showed a net neutralization effect on Ad5 in HeLa cells, whereas the FNIII icosapeptide RHILWTPANTPAMGYLARVS significantly increased Ad5 binding to HeLa cells. Daudi cells, which lack surface expression of HLA class I molecules, showed a weak capacity for Ad5 binding. In β2‐microglobulin‐transfected Daudi cells, Ad5 attachment and permissivity were restored to HeLa cell levels, with 4000 receptors per cell and a binding constant of 1.4×1010/M. The results suggested that the conserved region of MHC‐I α2‐domain including Trp167 represents a high affinity receptor for Ad5 fiber knob, whereas ubiquitous FNIII modules would serve as auxiliary receptors.

Effects of bronchopulmonary inflammation induced by Pseudomonas aeruginosa on adenovirus-mediated gene transfer to airway epithelial cells in mice

“…37 Therefore, viral surface proteins or their cellular surface receptor(s) may undergo proteolysis by neutrophil elastase and/or damage by oxidants in secretions of infected airways. These proteins include the fiber protein of the viral capsid and its receptors on host cells, 38 including the recently described coxsackievirus and adenovirus receptor (CAR) 39 and the alpha-2 domain of major histocompatibility (MHC) class I, 40 in addition to the penton base complex of viral capsid and the ␣ v ␤3 and ␣ v ␤5 integrins on the host cell membrane. 41 Of further interest is the observation that P. aeruginosa has been found to upregulate the expression of the mucin gene MUC 2.…”

An interaction between penton base and αv integrins plays a minimal role in adenovirus-mediated gene transfer to hepatocytes in vitro and in vivo

“…Such studies have established the importance of interactions between the viral fiber and penton base proteins, and the fiber receptors [9][10][11][12] and ␣v integrins 13-17 on the cell surface. However, there is less knowledge about the importance of these interactions in cells that are targets for gene therapy.…”

“…First, the adenovirus fiber protein recognizes a receptor on the cell membrane. [9][10][11][12] Second, viral penton base binds to ␣v␤3 or ␣v␤5 integrins. 13,14 The interaction of penton base with cell surface integrins is thought to have several effects.…”

Imaging and tissue biodistribution of 99mTc-labeled adenovirus knob (serotype 5)

“…[11][12][13] Two receptors for Ad5 have been identified. 14,15 Following attachment, the next step in infection by Ad2 and Ad5 is internalization of the virion by receptor-mediated endocytosis, a process involving the lower affinity of Arg-Gly-Asp (RGD) peptide sequences in the penton base to secondary host cell receptors, integrins ␣ v ␤ 3 and ␣ v ␤ 5 . 16,17 Thus, the major determinant of Ad tropism is the initial high-affinity interaction between the knob domain of the fiber protein and its cognate cellular receptor.…”