Vero cells were plated at an initial seeding density of 1610 5 / well in 12-well plates. One day later cells were infected with GV or NSDV at a multiplicity of infection (MOI) of 1. The virus inoculum was removed one hour after infection, cells were washed once with PBS and fresh medium was added. The infected cells were further incubated for 14 h before being treated with 1000 IU/ml recombinant human aA-Interferon (IFN) or 1000 IU/ml recombinant human IFN-c. IFN-aA was purchased from Calbiochem and IFN-c was obtained from Millipore. Cells were treated for 30 min with or without IFN before being harvested and lysed with 100 ml of 1x SDS sample buffer (New England Biolabs). SDS-PAGE and Western blots were carried out as previously described [64] . A Human Monoclonal Antibody with Neutralizing Activity against Highly Divergent Influenza Subtypes The interest in broad-range anti-influenza A monoclonal antibodies (mAbs) has recently been strengthened by the identification of anti-hemagglutinin (HA) mAbs endowed with heterosubtypic neutralizing activity to be used in the design of “universal” prophylactic or therapeutic tools. However, the majority of the single mAbs described to date do not bind and neutralize viral isolates belonging to highly divergent subtypes clustering into the two different HA-based influenza phylogenetic groups: the group 1 including, among others, subtypes H1, H2, H5 and H9 and the group 2 including, among others, H3 subtype. Here, we describe a human mAb, named PN-SIA28, capable of binding and neutralizing all tested isolates belonging to phylogenetic group 1, including H1N1, H2N2, H5N1 and H9N2 subtypes and several isolates belonging to group 2, including H3N2 isolates from the first period of the 1968 pandemic. Therefore, PN-SIA28 is capable of neutralizing isolates belonging to subtypes responsible of all the reported pandemics, as well as other subtypes with pandemic potential. The region recognized by PN-SIA28 has been identified on the stem region of HA and includes residues highly conserved among the different influenza subtypes. A deep characterization of PN-SIA28 features may represent a useful help in the improvement of available anti-influenza therapeutic strategies and can provide new tools for the development of universal vaccinal strategies. Influenza, one of the diseases that has shaped human history [1, 2] , still has an evident clinical and socio-economical impact [3, 4] . The 2009 pandemic has raised several major concerns related to the few prophylactic and therapeutic measures available. Antiviral compounds have drawbacks caused by the rapid emergence of drug-resistant isolates [5, 6] , require prompt administration to be effective [7] , and have several associated side-effects especially in high-risk categories, including children and pregnant women [8, 9] . Additionally, the vaccinal strategy is exposed to the annual risk of being ineffective due to possible mismatches between the predicted strains included in the vaccine and those actually in circulation; moreover, it would not engender a prompt response in pandemic settings [10] . In this scenario, new broadrange ''universal'' anti-influenza strategies are required [11, 12] . In particular, it would be important to identify and eventually elicit what has recently been described as an unusually extreme broadrange immunity directed against broadly conserved viral regions, differing from the more common and restricted immunity directed against highly variable regions [12] . A number of approaches have already been proposed in literature [10, 12, 13, 14, 15, 16] , but a pivotal role, both in the prophylactic and therapeutic field, may be played by the availability of broad-range neutralizing human monoclonal antibodies (mAbs) allowing the identification of human B epitopes widely shared among different influenza subtypes [11, 12] . Indeed, it is accepted that antibodies are key players in natural protection against influenza viruses, and that hemagglutinin (HA) is the main target for the virus-neutralizing antibody response [17] . However, although a single influenza infection provides lifelong immunity against the infecting virus and a limited number of antigenically correlated strains, the host can remain susceptible to infection with an antigenically drifted variant due to HA variability [18] .