IntroductionThe hypoxia-inducible factor (HIF) pathway plays a protective role in regulating genes that mitigate the effects of low oxygen tension. Under normoxic conditions, oxygen-sensitive HIF-␣ isoforms are rendered inactive via proline hydroxylation by HIF-specific prolyl hydroxylases (HIF-PHs), which lead to binding of von HippelLindau protein and targeted degradation through the ubiquitinproteasome pathway. Under hypoxic conditions, where less oxygen substrate is available for proline hydroxylation by HIF-PHs, HIF-␣ isoforms are stabilized, heterodimerize with HIF-␤, and translocate to the nucleus where they bind to hypoxia-responsive element (HRE) motifs. [1][2][3] In cooperation with other transcriptional coactivators, HIF induces transcription of genes that ameliorate the effects of hypoxia, including EPO and its receptor, transferrin and its receptor, glucose transporters and glycolytic enzymes, and vascular endothelial growth factor (VEGF). 4 A relationship between fetal hemoglobin (HbF) levels and hypoxia has been reported for nearly half a century: increased HbF levels are associated with intrauterine hypoxia, 5 maternal smoking, 6 postnatal hypoxemia from congenital heart disease, 7,8 and anemia of prematurity. 9 Additionally, infants born at high altitude demonstrate enhanced erythropoiesis and elevated HbF levels compared with infants born at sea level. 10 Evidence for postnatal induction of HbF through a hypoxia pathway also exists in several species. Camelids adapt to hypoxia through increased fetal hemoglobin levels, with adult alpacas demonstrating HbF levels of 55% at high altitude. 11 In young baboons, significant increases in HbF levels occurred after phenylhydrazine induced hemolysis or hypobaric hypoxia. 12 While the magnitude of the HbF response may be genetically determined, 13 HbF levels could be maintained longterm by continued erythropoietic stress. 14 Indeed, a relationship between the HIF pathway and HbF expression has been proposed recently, and putative HIF-binding sites have been described in the locus control region of the globin gene cluster. 15 Thus modulating HIF-␣, the critical and labile subunit(s) in the HIF pathway orchestrating the response to hypoxia, represents a new direction to investigate for HbF induction.Stabilization of HIF-␣ through inhibition of HIF-PHs may have therapeutic potential in the treatment of the ␤-hemoglobinopathies. For example, the hypoxic environment during fetal development is protective for individuals with sickle cell anemia; however, following the transition to normoxia at birth, fetal hemoglobin levels fall with a gradual replacement of the ␥-globin chain by the abnormal ␤-globin chain, rendering the pathologic hemoglobin (Hb) tetramer prone to polymerization upon deoxygenation. The polymerized Hb leads to impaired deformability and sickling of red blood cells, which lodge in end arterioles, producing the classic and most prominent feature of the disorder, repeated vasoocclusive crises. Individuals who coinherit mutations resulting in her...

Infection models were developed for adult cows and for young calves using the same strain of bovine coronavirus (BCV), which for the first time allows experimental reproduction of winter dysentery (WD) in seronegative lactating cows. The cattle were infected through direct contact with an experimentally inoculated calf. All experimental cattle shed faecal BCV with development of diarrhoea, being profusely watery with small amounts of blood in the most severely affected animals, including both cows and calves. The cows, in contrast to the calves, showed depressed general condition and appetite leading to a marked decrease in milk yield. Further age-associated differences were a shorter incubation period in the two youngest calves, but with milder fever and milder decrease in white blood cell counts. These findings shed light on the apparent epidemiological differences between WD and calf BCV diarrhoea suggesting that, (1) the same strains of BCV cause natural outbreaks of calf diarrhoea and WD, (2) seronegative cows are more severely affected by the infection than seronegative conventionally reared calves, and (3) unaffected general condition in diarrhoeic calves may lead to underestimation of the occurrence of calf diarrhoea in WD outbreaks. In response to infection, all cattle produced early interferon type 1 in serum and, except for one calf, in nasal secretions. A finding not previously reported is the detection of interferon type 1 responses in bovine milk. All cattle developed high IgM antibody responses and long-lasting IgA antibody responses both systemically and locally. The serum IgM antibody responses came earlier in most of the calves than in the cows. Prolonged IgM antibody responses were detected in serum and milk, while those in nasal secretions were much shorter. BCV-specific IgA was present in nasal secretions from all cattle throughout the 6 months follow-up. The IgA antibody response in serum was detected up to 17 months post-infection and the duration showed an age-related variation indicating a more prominent IgA memory in the adult cattle and in the older calves than in the younger ones. BCV-specific IgG was detected in all cattle during the experimental period of up to 22 months. In conclusion, WD was reproduced in seronegative lactating cows. The cows showed a more severe general diseases than seronegative calves infected concurrently. Very long-lasting IgA antibody responses were detected both systemically and locally.

The post-exposure therapeutic efficacy of injectable peramivir against highly pathogenic avian influenza type A H5N1 was evaluated in mice and in ferrets. Seventy to eighty percent of the H5N1-infected peramivir-treated mice, and 70% in the oseltamivir treated mice survived the 15-day study period, as compared to 36% in control (vehicle) group. Ferrets were infected intranasally with H5N1 followed by treatment with multiple doses of peramivir. In two of three trials, a statistically significant increase in survival over a 16-18 day period resulted from peramivir treatment, with improved survival of 40-64% in comparison to mock-treated or untreated animals. Injected peramivir mitigates virus-induced disease, reduces infectious virus titers in the lungs and brains and promotes survival in ferrets infected intranasally with this highly neurovirulent isolate. A single intramuscular peramivir injection protected mice against severe disease outcomes following infection with highly pathogenic avian influenza and multi-dose treatment was efficacious in ferrets.

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Argentine hemorrhagic fever (AHF), a systemic infectious disease caused by infection with Junin virus, affects several organs, and patients can show hematologic, cardiovascular, renal, or neurologic symptoms. We compared the virulence of two Junin virus strains in inbred and outbred guinea pigs with the aim of characterizing this animal model better for future vaccine/antiviral efficacy studies. Our data indicate that this passage of the XJ strain is attenuated in guinea pigs. In contrast, the Romero strain is highly virulent in Strain 13 as well as in Hartley guinea pigs, resulting in systemic infection, thrombocytopenia, elevated aspartate aminotransferase levels, and ultimately, uniformly lethal disease. We detected viral antigen in formalin-fixed, paraffin-embedded tissues. Thus, both guinea pig strains are useful animal models for lethal Junin virus (Romero strain) infection and potentially can be used for preclinical trials in vaccine or antiviral drug development.

During the last decade, alphaviruses became widely used for expression of heterologous genetic information and development of recombinant vaccines against a variety of human and animal pathogens. In this study, we compared a number of vectors based on the genome of Sindbis (SINV) and Venezuelan equine encephalitis (VEEV) viruses for their ability to express the Rift Valley fever virus (RVFV) envelope glycoprotein Gn and induce a protective immune response against RVFV infection. Our results suggest that (i) application of VEEV-based expression systems appears to be advantageous, when compared to similar systems designed on the basis of the SINV genome. (ii) Alphavirus-specific E3 and E2 proteins and furin-specific cleavage sites can be used for engineering secreted forms of the proteins. (iii) Alphaviruses can be modified for expression of the large fragments of heterologous proteins on the surface of chimeric, infectious viral particles. Thus, alphavirus-based expression systems may have the potential for a broader application beyond their current use as replicons or double-subgenomic vectors.

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