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Adenovirus Serotype 5 Infects Human Dendritic Cells via a CAR-Independent Receptor Pathway Mediated by Lactoferrin and DC-SIGN

¹ Karolinska Institutet;
² TNO Biosciences;
³ Crucell Holland;
⁴ National Institutes of Health

⁵ E-mail: karin.lore{at}ki.se

The coxsackievirus and adenovirus receptor (CAR) is the described primary receptor for Adenovirus serotype 5 (Ad5), a common human pathogen that has been exploited as a viral vector for gene therapy and vaccination. Here, we report that monocytes and dendritic cells (DCs) such as freshly isolated human blood myeloid DCs, plasmacytoid DCs, and monocyte-derived DCs are susceptible to recombinant Ad5 (rAd5) infection despite their lack of CAR expression. Langerhans cells and dermal DCs from skin express CAR but blocking CAR only partly decreased rAd5 infection, together suggesting that other receptor pathways mediate viral entry of these cells. Lactoferrin (Lf), an abundant protein in many bodily fluids known for its anti-viral and anti-bacterial properties, promoted rAd5 infection in all cell populations except plasmacytoid DCs using a CAR-independent process. Lf phenotypically differentiated the DCs but cell activation only played a minor role in the increase in infection frequencies. The C-type lectin receptor DC-SIGN facilitated viral entry of rAd5-Lf complexes and this was dependent on high-mannose type N-linked glycans on Lf. We therefore speculate that Lf present at high levels at mucosal sites can facilitate rAd5 attachment and enhance infection of DCs. A better understanding of the tropism and receptor mechanisms of Ad5 can help explain Ad5 pathogenesis and guide the engineering of improved rAd vectors.

Received 29 October 2008; accepted 10 March 2009.