Influenza pandemics occur unpredictably when zoonotic influenza viruses with novel antigenicity acquire the ability to transmit amongst humans 1 . Incompatibilities between avian virus components and the human host limit host range breaches. Barriers include receptor preference, virion stability and poor activity of the avian virus RNA-dependent RNA polymerase in human cells 2 . Mutants of the heterotrimeric viral polymerase components, particularly PB2 protein, are selected during mammalian adaptation, but their mode of action is unknown [3][4][5][6] . We show that a species-specific difference in host protein ANP32A accounts for the suboptimal function of avian virus polymerase in mammalian cells. Avian ANP32A possesses an additional 33 amino acids between the LRR and LCAR domains. In mammalian cells, avian ANP32A rescued the suboptimal function of avian virus polymerase to levels similar to mammalian adapted polymerase. Deletion of the avian-specific sequence from chicken ANP32A abrogated this activity whereas its insertion into human ANP32A, or closely related ANP32B, supported avian virus polymerase function. Substitutions, such as PB2 E627K, rapidly selected upon infection of humans with avian H5N1 or H7N9 influenza viruses, adapt the viral polymerase for the shorter

The impact of avian influenza caused by H9N2 viruses in Pakistan is now significantly more severe than in previous years. Since all gene segments contribute towards the virulence of avian influenza virus, it was imperative to investigate the molecular features and genetic relationships of H9N2 viruses prevalent in this region. Analysis of the gene sequences of all eight RNA segments from 12 viruses isolated between 2005 and 2008 was undertaken. The hemagglutinin (HA) sequences of all isolates were closely related to H9N2 viruses isolated from Iran between 2004 and 2007 and contained leucine instead of glutamine at position 226 in the receptor binding pocket, a recognised marker for the recognition of sialic acids linked α2–6 to galactose. The neuraminidase (NA) of two isolates contained a unique five residue deletion in the stalk (from residues 80 to 84), a possible indication of greater adaptation of these viruses to the chicken host. The HA, NA, nucleoprotein (NP), and matrix (M) genes showed close identity with H9N2 viruses isolated during 1999 in Pakistan and clustered in the A/Quail/Hong Kong/G1/97 virus lineage. In contrast, the polymerase genes clustered with H9N2 viruses from India, Iran and Dubai. The NS gene segment showed greater genetic diversity and shared a high level of similarity with NS genes from either H5 or H7 subtypes rather than with established H9N2 Eurasian lineages. These results indicate that during recent years the H9N2 viruses have undergone extensive genetic reassortment which has led to the generation of H9N2 viruses of novel genotypes in the Indian sub-continent. The novel genotypes of H9N2 viruses may play a role in the increased problems observed by H9N2 to poultry and reinforce the continued need to monitor H9N2 infections for their zoonotic potential.

H9N2 avian influenza viruses have become globally widespread in poultry over the last two decades and represent a genuine threat both to the global poultry industry but also humans through their high rates of zoonotic infection and pandemic potential. H9N2 viruses are generally hyperendemic in affected countries and have been found in poultry in many new regions in recent years. In this review, we examine the current global spread of H9N2 avian influenza viruses as well as their host range, tropism, transmission routes and the risk posed by these viruses to human health.

H9N2 avian influenza viruses have become globally widespread in poultry over the last two decades and represent a genuine threat both to the global poultry industry but also humans through their high rates of zoonotic infection and pandemic potential. H9N2 viruses are generally hyperendemic in effected countries and have been found in poultry in many new regions in recent years. In this review we examine the current global spread of H9N2 avian influenza viruses as well as their host range, tropism, transmission routes and the risk posed by these viruses to human health.

Production of alpha/beta interferon in response to viral double-stranded RNA (dsRNA) produced during viral replication is a first line of defense against viral infections. Here we demonstrate that the E rns glycoprotein of the pestivirus bovine viral diarrhea virus can act as an inhibitor of dsRNA-induced responses of cells. This effect is seen whether E rns is constitutively expressed in cells or exogenously added to the culture medium. The E rns effect is specific to dsRNA since activation of NF-B in cells infected with Semliki Forest virus or treated with tumor necrosis factor alpha was not affected. We also show that E rns contains a dsRNA-binding activity, and its RNase is active against dsRNA at a low pH. Both the dsRNA binding and RNase activities are required for the inhibition of dsRNA signaling, and we discuss here a model to account for these observations. Bovine viral diarrhea virus (BVDV) is a Pestivirus belonging to the family Flaviviridae and is a major pathogen of cattle throughout the world with an incidence of infection often in excess of 70% (9, 24). An unusual feature of pestiviruses is their ability to sustain a persistent infection after in utero infection of a fetus. BVDV exists as two biotypes according to their cytopathogenicity on cultured cells, and the ability to sustain a persistent infection is exclusively a property of the noncytopathogenic BVDV biotype. Persistently infected calves born after infection of the fetus during the early stages of pregnancy are held to be the source of acute virus infection and the subsequent generation of cytopathogenic BVDV variants isolated from animals with mucosal disease. Survival of the virus in the fetus requires avoiding immune responses; since the acquired immune response is not developed early in embryogenesis, innate immune responses are the main host defenses from infection. Evasion of innate immunity in the fetus is at least in part due to the lack of alpha/beta interferon (IFN-␣/␤) production after noncytopathogenic BVDV infection (6). We and others have shown that cultured cells infected with noncytopathogenic BVDV are refractory to the IFN-inducing effects of infection with heterologous virus or the addition of double-stranded RNA (dsRNA) to cells (3, 30). Thus, noncytopathogenic BVDV takes active measures to block the production of IFN-␣/␤. A key component of this inhibition operates at the level of inhibiting the DNA-binding activity of the IFN regulatory transcription factor IRF-3 induced by heterologous virus infection (2).The viral gene products associated with the evasion of the IFN system have not been identified. The virus genome is positivestrand RNA that is translated to form a single virus polyprotein, which, through cleavage by both host and virus proteases, gives rise to either 11 or 12 mature viral proteins (NH2-Npro-C-E rns -E1-E2-p7-NS2-NS3-NS4A-NS4B-NS5A-NS5B-COOH), dependent on the virus biotype (20). E rns , E1, and E2 are glycoproteins found on the surface of the viron (35). In addition to being a virion protein, a p...