Important advancements in the development of novel mouse/human chimeras through the engraftment of human immune cells and tissues into immunodeficient mice, including the recently described humanized BLT mouse model, holds great promise to facilitate the in vivo study of human immune responses. However, little data exists regarding the extent to which cellular immune responses in humanized mice accurately reflect those seen in humans. As a model pathogen we infected humanized BLT mice with HIV-1 and characterized HIV-1-specific immune responses and viral evolution during the acute phase of infection. HIV-1-specific CD8+ T cell responses in these mice were found to closely resemble those in humans in terms of their specificity, kinetics and immunodominance. Viral sequence evolution also revealed rapid and highly reproducible escape from these responses, mirroring the adaptations to host immune pressures observed during natural HIV-1 infection. Moreover, mice expressing the protective HLA-B*57 allele exhibited enhanced control of viral replication, and restricted the same CD8+ T cell responses to conserved regions of HIV-1 Gag that are critical to its control of HIV-1 in humans. These data reveal that the humanized BLT mouse model appears to accurately recapitulate human pathogen-specific cellular immunity and the fundamental immunological mechanisms required to control a model human pathogen, aspects critical to the utility of a small animal model for human pathogens.

Selective breeding for desirable traits in strictly controlled populations has generated an extraordinary diversity in canine morphology and behaviour, but has also led to loss of genetic variation and random entrapment of disease alleles. As a consequence, specific diseases are now prevalent in certain breeds, but whether the recent breeding practice led to an overall increase in genetic load remains unclear. Here we generate whole genome sequencing (WGS) data from 20 dogs per breed from eight breeds and document a ~10% rise in the number of derived alleles per genome at evolutionarily conserved sites in the heavily bottlenecked cavalier King Charles spaniel breed (cKCs) relative to in most breeds studied here. Our finding represents the first clear indication of a relative increase in levels of deleterious genetic variation in a specific breed, arguing that recent breeding practices probably were associated with an accumulation of genetic load in dogs. We then use the WGS data to identify candidate risk alleles for the most common cause for veterinary care in cKCs–the heart disease myxomatous mitral valve disease (MMVD). We verify a potential link to MMVD for candidate variants near the heart specific NEBL gene in a dachshund population and show that two of the NEBL candidate variants have regulatory potential in heart-derived cell lines and are associated with reduced NEBL isoform nebulette expression in papillary muscle (but not in mitral valve, nor in left ventricular wall). Alleles linked to reduced nebulette expression may hence predispose cKCs and other breeds to MMVD via loss of papillary muscle integrity.

The emerging field of translational safety genetics is providing new opportunities to enhance drug discovery and development. Genetic variation in therapeutic drug targets, off-target interactors and relevant drug metabolism/disposition pathways can contribute to diverse drug pharmacologic and toxicologic responses between different animal species, strains and geographic origins. Recent advances in the sequencing of rodent, canine, nonhuman primate, and minipig genomes have dramatically improved the ability to select the most appropriate animal species for preclinical drug toxicity studies based on genotypic characterization of drug targets/pathways and drug metabolism and/or disposition, thus avoiding inconclusive or misleading animal studies, consistent with the principles of the 3Rs (replacement, reduction and refinement). The genetic background of individual animals should also be taken into consideration when interpreting phenotypic outcomes from toxicity studies and susceptibilities to spontaneous safety-relevant background findings.

Sequence analyses show that the outbreak of pandemic (H1N1) 2009 resulted from the spread of a recently derived hemagglutinin through a population of ancient and more diverse neuraminidase segments. This pattern implies reassortment and suggests that the novel form of hemagglutinin conferred a selective advantage.

Chaos Game Representation (CGR) is an iterative mapping technique, which shows patterns in amino acids or nucleotide sequences. Here we present a method for using CGR to explore evolutionary relationships of protein sequences based on amino acid properties and illustrate the approach with complete sets of protein translations from viral genomes. In an analysis of complete polyprotein sequences from the viral family Flaviviridae, the CGR method was able to cluster members of major viral groups together, but relations within groups were not well resolved in comparison to an alignment-based phylogeny. We applied the method to members of five different families of ssRNA positive-strand viruses, and each family formed a distinct cluster. We also present a method of testing the reliability of clustering in CGR-based trees, which involves the use of multiple random starting points for the CGR process.