Respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) cause a similar spectrum of respiratory infections in humans. Classified within the Paramyxoviridae family, Pneumovirinae subfamily, RSV and hMPV present a significant degree of divergence in genome constellation, organization, and protein sequences. RSV has been reported to be a poor inducer of alpha/beta interferons (IFN-␣/␤) and partially resistant to its antiviral activity. The nature of the innate immune response to hMPV is currently unknown. Herein, an experimental mouse model was used to investigate the interplay between RSV and hMPV infections and IFN-␣ in the airways. RSV-infected BALB/c mice treated intranasally with either poly-ICLC, a potent inducer of IFN-␣, or directly with recombinant IFN-␣ showed significantly reduced lung viral titers, inflammation, and clinical disease than untreated controls. However, RSV was significantly less sensitive to the antiviral activity of IFN-␣ than hMPV. Similarly, when the ability to directly induce IFN-␣ production was assessed, RSV was clearly a weaker inducer of IFN-␣ than hMPV, as shown by both kinetics and the absolute amount of IFN-␣ secreted into the bronchoalveolar lavage. To further investigate the putative inhibitory effect of these viruses on IFN-␣ production, mice were infected for 48 h prior to treatment with poly-ICLC or a specific Toll-like receptor 9 ligand, CpG oligodeoxynucleotides. Strikingly, both poly-ICLC-and CpG-mediated IFN-␣ production was abrogated by either RSV or MPV infection. These results suggest that a complex interplay between virus-specific and host-mediated responses regulates IFN-␣ in the lung during infection by members of the Pneumovirinae family.

Eastern equine encephalitis virus (EEEV) causes human encephalitis in North America (NA), but in South America (SA) it has rarely been associated with human disease, suggesting that SA strains are less virulent. To evaluate the hypothesis that this virulence difference is due to a greater ability of NA strains to evade innate immunity, we compared replication of NA and SA strains in Vero cells pretreated with interferon (IFN). Human IFN-␣, -␤, and -␥ generally exhibited less effect on replication of NA than SA strains, supporting this hypothesis. In the murine model, no consistent difference in IFN induction was observed between NA and SA strains. After infection with most EEEV strains, higher viremia levels and shorter survival times were observed in mice deficient in IFN-␣/␤ receptors than in wild-type mice, suggesting that IFN-␣/␤ is important in controlling replication. In contrast, IFN-␥ receptor-deficient mice infected with NA and SA strains had similar viremia levels and mortality rates to those of wild-type mice, suggesting that IFN-␥ does not play a major role in murine protection. Mice pretreated with poly(I-C), a nonspecific IFN inducer, exhibited dose-dependent protection against fatal eastern equine encephalitis, further evidence that IFN is important in controlling disease. Overall, our in vivo results did not support the hypothesis that NA strains are more virulent in humans due to their greater ability to counteract the IFN response. However, further studies using a better model of human disease are needed to confirm the results of differential human IFN sensitivity obtained in our in vitro experiments.

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Salivary transmission by the 30 million human immunodeficiency virus (HIV) carriers is rare, despite kissing, aerosolization, and dental treatment. The main protective mechanism of saliva is reported to be inactivation of HIV-transmitting leukocytes by its unique hypotonicity; however, the successful oral transmission of HIV by seminal fluid and milk is unexplained. Whether seminal fluid and milk successfully transmit HIV orally by overcoming the recipient's salivary hypotonic inactivation of HIV-transmitting leukocytes was tested. Isotonic salt solution and normal donor samples of milk, colostrum, seminal fluid, and blood were studied for their ability to overcome the salivary hypotonic inactivation. All samples, in physiologic volumes, prevented the hypotonic saliva from inactivating HIV-transmitting leukocytes by providing solutes and retarding diffusion. This indicates that successful oral transmission of HIV by seminal fluid, milk, and colostrum may be due to their isotonicity, which overcomes hypotonic salivary inactivation of HIV-transmitting leukocytes.

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