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. 2004 Oct 26;101(43):15470-5.
doi: 10.1073/pnas.0406821101. Epub 2004 Oct 19.

Cellular integrins function as entry receptors for human cytomegalovirus via a highly conserved disintegrin-like domain

Adam L Feire  1 , Heidi Koss, Teresa Compton
Affiliations

Cellular integrins function as entry receptors for human cytomegalovirus via a highly conserved disintegrin-like domain

Adam L Feire et al. Proc Natl Acad Sci U S A. .

Abstract

Human cytomegalovirus (HCMV) is capable of manifesting disease in nearly every organ system in immunocompromised patients. This broad pathogenic tropism correlates with the ability of the virus to infect all tested vertebrate cell types in vitro, a characteristic that has made receptor identification extremely difficult. During virus entry, HCMV induces cellular morphological changes and signaling cascades consistent with engagement of cellular integrins; however, HCMV structural proteins do not possess the widely used RGD integrin-binding motif. We identified an integrin-binding disintegrin-like domain within HCMV envelope glycoprotein B, a protein required for virus entry and fusion throughout the Herpesviridae. Accepted receptor criteria are met through the use of function-blocking integrin Abs, beta1 integrin knockout mouse fibroblasts, and glycoprotein B disintegrin-like peptides, all of which support a critical role for alpha2beta1, alpha6beta1, and alphaVbeta3 integrins as HCMV entry receptors and signaling mediators acting during the penetration stage of the entry pathway. Strikingly, the glycoprotein B disintegrin-like domain is conserved in many human and animal herpesviruses, suggesting that integrins may support entry across this medically important virus family.

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Figures

Fig. 1.
Fig. 1.
Conservation of the gB disintegrin-like domain. Alignment of the 20 amino acids encompassing the gB disintegrin-like domain of representative herpesviruses. The conserved herpesvirus gB disintegrin-like consensus sequence is highlighted in red, whereas β herpesvirus conservation is highlighted in gray. The canonical ADAM family disintegrin loop is shown above.
Fig. 2.
Fig. 2.
HCMV gB disintegrin-like peptide inhibits CMV infection. (A) NHDFs were treated with the indicated peptides before HCMV challenge (moi, 0.5 pfu per cell). (B) The 3T3 or NHDFs were treated with the indicated peptides before virus challenge. Shown is the number of infected foci per 1,000 cells counted.
Fig. 3.
Fig. 3.
Integrin-neutralizing Abs inhibit HCMV infectivity. (A–C) Integrin-neutralizing Abs were added to NHDFs before HCMV infection (moi, 0.5 pfu per cell). Infectivity was determined by immediate early gene expression with infected foci per 1,000 cells shown. (D) β1 integrin knockout fibroblasts (GD25) or GD25 cells with β1 integrin expression restored (GD25β1) were treated with virus, and infected foci were scored. (E and F) GD25, GD25β1, NHDF, or 3T3 cells were treated with β1, β3, or β1 plus β3 Abs followed by HCMV or MCMV infection (moi, 0.5 pfu per cell). Infectivity was determined by e1 (MCMV) or immediate early (HCMV) gene expression, with infected foci per 1,000 cells counted shown.
Fig. 4.
Fig. 4.
Effect of integrin-blocking treatments on virus binding and entry. (A) HCMV gB disintegrin-like or null peptides, integrin-neutralizing Abs, or soluble heparin were added to NHDFs at 4°C, followed by infection with HCMV. Attachment was measure by gB ELISA. (B) NHDFs were treated with indicated integrin Abs, infected with HCMV, and assayed for pp65 localization. The number of pp65-positive cells per 1,000 cells is shown.
Fig. 5.
Fig. 5.
Effect of HCMV on the activation of integrin signaling. (A and B) NHDFs were serum-starved and challenged with LPA or HCMV as indicated. (C and D) Samples were blotted with phosphospecific polyclonal anti-integrin β1 [pTpT 788/789] or P-FAK to demonstrate differential activated levels. NHDF (C), GD25 (D Left), or GD25β1(D Right) cells were stimulated as indicated for 10 min. Cells were fixed and stained with phalloidin to visualize the actin cytoskeleton. Arrows indicate cell rounding, filopodia, and stress fiber formation.
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References

    1. Ljungman, P. (1996) Scand. J. Infect. Dis. Suppl. 100, 59-63. - PubMed
    1. Ramsay, M. E., Miller, E. & Peckham, C. S. (1991) Arch. Dis. Child. 66, 1068-1069. - PMC - PubMed
    1. Sinzger, C., Kahl, M., Laib, K., Klingel, K., Rieger, P., Plachter, B. & Jahn, G. (2000) J. Gen. Virol. 81, 3021-3035. - PubMed
    1. Ibanez, C. E., Schrier, R., Ghazal, P., Wiley, C. & Nelson, J. A. (1991) J. Virol. 65, 6581-6588. - PMC - PubMed
    1. Nowlin, D. M., Cooper, N. R. & Compton, T. (1991) J. Virol. 65, 3114-3121. - PMC - PubMed

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