Human hematopoietic (CD34+) stem cells possess high-affinity receptors for adenovirus type 11p

Abstract

Gene transfer into human hematopoietic stem cells using Ad5 is inefficient due to lack of the primary receptor CAR and the secondary receptors alphavbeta3 integrin and alphavbeta5 integrin, and due to the high seroprevalence of Ad5 antibodies in most adults, resulting in diminished gene transduction. In the present study, we screened six species (species A-F) of adenovirus, displaying different tropisms for interaction with CD34+ cells, at the level of virus attachment and expression. Virus particles were biotinylated and their binding capacity was determined by FACS analysis using streptavidin-FITC. Ad11p, Ad35, and Ad3 (species B) showed high binding affinity, while Ad7, Ad11a (species B), and Ad37 (species D) displayed intermediate affinity. Virions of Ad4 (species E), Ad5 (species C), Ad31 (species A), and Ad41 (species F) hardly bound to hematopoietic progenitor cells. Using a double-labeling system, we demonstrated that adenoviruses bind to quiescent CD34+ cells. Ad11p virions showed the highest affinity among the adenoviruses detected. We further confirmed that virus fiber-specific receptors were present on the hematopoietic progenitor cell surface, because both recombinant fiber of Ad11p and specific antiserum against rfiber could block virus attachment. The ability of the adenoviruses to infect hematopoietic cells was studied by immunofluorescence staining. The adenoviruses from species B and Ad37 showed higher infectivity than Ad31, Ad5, Ad4, and Ad41. Among the studied species B adenoviruses, Ad11p manifested a superior infectivity. Thus, we have confirmed that these cells have high-affinity receptors for species B:2 human adenovirus, Ad11p, and this virus may be used as candidate vector to target therapeutic genes to hematopoietic stem cells.

A New Group B Adenovirus Receptor Is Expressed at High Levels on Human Stem and Tumor Cells

“…Although a series of data were indicative of a role for integrins in Ad group II and III binding, blocking studies with integrin-specific antibodies and siRNA did not support this indication. Furthermore, despite the fact that quiescent CD34 ϩ cells express very small amounts of ␣v integrins, Ad3 binding to and infection of hematopoietic cells were efficient (23). While receptor X appears to be expressed on hematopoietic cells, it seem to be lost upon differentiation as Ad3 does not efficiently bind anymore to peripheral blood mononuclear cells (33) or DC (see Table 2).…”

Interaction of penton base Arg-Gly-Asp motifs with integrins is crucial for adenovirus serotype 35 vector transduction in human hematopoietic cells

“…In particular, hematopoietic cells, which are important targets for gene therapy but resistant to Ad5 vectors, are susceptible to subgroup B Ads. [13][14][15] Infection of subgroup B Ads is initiated by the attachment of the fiber knob to short consensus repeats 1 and 2 of human CD46. [16][17][18] However, the infection process of subgroup B Ads following binding to CD46 is poorly understood.…”

Antiadenoviral Effect of the α5β1 Integrin Receptor Ligand, GRGDSP Peptide, in Serotypes That Cause Acute Keratoconjunctivitis

“…A possible explanation for the ineffectiveness of GRGDSP peptide in AdV4 may be derived from the fact that AdV4 manifests superior binding and infectivity in epithelial A549 cells compared to members of group B and group D [28]. In contrast, AdVs from group B and group D show higher infectivity against human hematopoietic cells than AdV4 [29]. These biological properties of AdV4 in various cells suggest that AdV4 has a superior CAR capacity or uses an unknown coreceptor in addition to CAR, leading to its lower susceptibility to the GRGDSP peptide.…”