Prior Virus Exposure Alters the Long-Term Landscape of Viral Replication during Feline Lentiviral Infection

We developed a feline model of lentiviral cross-species transmission using a puma lentivirus (PLV or FIVPco) which infects domestic cats but does not cause disease. Infection with PLV protects cats from CD4+ T-cell decline caused by subsequent infection with virulent feline immunodeficiency virus (FIV). Previous studies implicate innate immune and/or cellular restriction mechanisms for FIV disease attenuation in PLV-infected cats. In this study, we evaluated viral infection and cytokine mRNA transcription in 12 different tissue reservoirs approximately five months post infection. We quantitated tissue proviral load, viral mRNA load and relative transcription of IL-10, IL-12p40 and IFNγ from tissues of cats exposed to FIV, PLV or both viruses and analyzed these parameters using a multivariate statistical approach. The distribution and intensity of FIV infection and IFNγ transcription differed between single and co-infected cats, characterized by higher FIV proviral loads and IFNγ expression in co-infected cat tissues. Variability in FIV mRNA load and IFNγ was significantly more constrained in co-infected versus singly infected cat tissues. Single-infected:co-infected ratios of FIV mRNA load compared to FIV proviral load indicated that active viral transcription was apparently inhibited during co-infection. These results indicate that previous PLV infection increases activation of tissue innate immunity and constrains the ability of FIV to productively infect tissue reservoirs of infection for months, independent of FIV proviral load, supporting a model in which innate immunity and/or modulation of target cell susceptibility play a key role in PLV-induced protection from FIV disease

High prevalence of Lynx rufus gammaherpesvirus 1 in wild Vermont bobcats

Gammaherpesviruses (GHVs) are host specific DNA viruses that infect a large range of mammalian species. These viruses preferentially target host lymphocyte cell populations and infection may lead to morbidity or mortality in immunocompromised, co-infected, or non-adapted hosts. In this study, we tested for the presence of Lynx rufus gammaherpesvirus 1 (LruGHV1) in a northeastern United States population of wild bobcats (L. rufus). We estimated prevalence of infection and viral load in infected individuals using quantitative real-time PCR analysis of spleen DNA from 64 Vermont bobcats. We observed an overall prevalence of 64% using this methodology. Bobcat age was significantly positively associated with GHV infection status, and we noted a trend for higher viral loads in young animals, but prevalence and viral load were similar in male and female bobcats. A single LruGHV1 variant was identified from the sequencing of the viral glycoprotein B gene of Vermont bobcats. This gene sequence was 100% similar to that reported in Florida bobcats and slightly variant from other isolates identified in the Western USA. Our work suggests broad geographic distribution and high prevalence of LruGHV1 in bobcat populations across the United States with infection attributes that suggest horizontal transmission of the agent. Geographic differences in viral genotype may reflect historical migration and expansion events among bobcat populations

Closing the gap on causal processes of infection risk from cross-sectional data:structural equation models to understand infection and co-infection

BACKGROUND: Epidemiological studies of disease exposure risk are frequently based on observational, cross-sectional data, and use statistical approaches as crucial tools for formalising causal processes and making predictions of exposure risks. However, an acknowledged limitation of traditional models is that the inferred relationships are correlational, cannot easily distinguish direct from indirect determinants of disease risk, and are often considerable simplifications of complex interrelationships. This may be particularly important when attempting to infer causality in patterns of co-infection through pathogen-facilitation. METHODS: We describe analyses of cross-sectional data using structural equation models (SEMs), a contemporary advancement on traditional regression approaches, based on our study system of feline gammaherpesvirus (FcaGHV1) in domestic cats. RESULTS: SEMs strongly supported a latent (host phenotype) variable associated with FcaGHV1 exposure and co-infection risk, suggesting these individuals are simply more likely to become infected with multiple pathogens. However, indications of pathogen-covariance (potential facilitation) were also variably detected: potentially among FcaGHV1, Bartonella spp and Mycoplasma spp. CONCLUSIONS: Our models suggest multiple exposures are primarily driven by host phenotypic traits, such as aggressive male phenotypes, and secondarily by pathogen-pathogen interactions. The results of this study demonstrate the application of SEMs to understanding epidemiological processes using observational data, and could be used more widely as a complementary tool to understand complex cross-sectional information in a wide variety of disciplines

Genetic identification of unique immunological responses in mice infected with virulent and attenuated Francisella tularensis

Francisella tularensis is a category A select agent based on its infectivity and virulence but disease mechanisms in infection remain poorly understood. Murine pulmonary models of infection were therefore employed to assess and compare dissemination and pathology and to elucidate the host immune response to infection with the highly virulent Type A F. tularensis strain Schu4 versus the less virulent Type B live vaccine strain (LVS). We found that dissemination and pathology in the spleen was significantly greater in mice infected with F. tularensis Schu4 compared to mice infected with F. tularensis LVS. Using gene expression rofiling to compare the response to infection with the two F. tularensis strains, we found that there were significant differences in the expression of genes involved in the apoptosis pathway, antigen processing and presentation pathways, and inflammatory response pathways in mice infected with Schu4 when compared to LVS. These transcriptional differences coincided with marked differences in dissemination and severity of organ lesions in mice infected with the Schu4 and LVS strains. Therefore, these findings indicate that altered apoptosis, antigen presentation and production of inflammatory mediators explain the differences in pathogenicity of F. tularensis Schu4 and LVS

Non-Fermi-liquid d-wave metal phase of strongly interacting electrons

Developing a theoretical framework for conducting electronic fluids qualitatively distinct from those described by Landau's Fermi-liquid theory is of central importance to many outstanding problems in condensed matter physics. One such problem is that, above the transition temperature and near optimal doping, high-transition-temperature copper-oxide superconductors exhibit `strange metal' behaviour that is inconsistent with being a traditional Landau Fermi liquid. Indeed, a microscopic theory of a strange-metal quantum phase could shed new light on the interesting low-temperature behaviour in the pseudogap regime and on the d-wave superconductor itself. Here we present a theory for a specific example of a strange metal---the 'd-wave metal'. Using variational wavefunctions, gauge theoretic arguments, and ultimately large-scale density matrix renormalization group calculations, we show that this remarkable quantum phase is the ground state of a reasonable microscopic Hamiltonian---the usual t-J model with electron kinetic energy $t$ and two-spin exchange $J$ supplemented with a frustrated electron `ring-exchange' term, which we here examine extensively on the square lattice two-leg ladder. These findings constitute an explicit theoretical example of a genuine non-Fermi-liquid metal existing as the ground state of a realistic model.Comment: 22 pages, 12 figures: 6 pages, 7 figures of main text + 16 pages, 5 figures of Supplementary Information; this is approximately the version published in Nature, minus various subedits in the main tex

Maize Cultivar Performance under Diverse Organic Production Systems

Maize (Zea mays L.) performance can vary widely between different production systems. The need for high-performing hybrids for organic systems with wide adaptation to various macroenvironments is becoming increasingly important. The goal of this study was to characterize inbred lines developed by distinct breeding programs for their combining ability and hybrid yield performance across diverse organic environments. Parent lines were selected from five different breeding programs to give a sample of publically available germplasm with potential for use in organic production systems with expired plant variety protection (Ex-PVP) and current commercial inbreds as benchmarks. A North Carolina Design II mating design was used to produce all possible cross combinations between seven lines designated as males and seven lines designated as females. A significantly positive general combining ability for the female inbred UHF134 suggests that it performs well in hybrid combination. Significant general combining ability was not observed for any male inbred line in this study. Several significantly positive specific combining abilities suggest that nonadditive genetic effects play an important role in determining yield in this germplasm. Further analysis revealed that hybrids containing either an Ex-PVP line or a commercial inbred line were on average superior to hybrids containing only inbreds developed by the cooperators of this study. This demonstrates the utility of testing inbreds from diverse sources when developing hybrids for organic production systems

Variable Fitness Impact of HIV-1 Escape Mutations to Cytotoxic T Lymphocyte (CTL) Response

Human lymphocyte antigen (HLA)-restricted CD8+ cytotoxic T lymphocytes (CTL) target and kill HIV-infected cells expressing cognate viral epitopes. This response selects for escape mutations within CTL epitopes that can diminish viral replication fitness. Here, we assess the fitness impact of escape mutations emerging in seven CTL epitopes in the gp120 Env and p24 Gag coding regions of an individual followed longitudinally from the time of acute HIV-1 infection, as well as some of these same epitopes recognized in other HIV-1-infected individuals. Nine dominant mutations appeared in five gp120 epitopes within the first year of infection, whereas all four mutations found in two p24 epitopes emerged after nearly two years of infection. These mutations were introduced individually into the autologous gene found in acute infection and then placed into a full-length, infectious viral genome. When competed against virus expressing the parental protein, fitness loss was observed with only one of the nine gp120 mutations, whereas four had no effect and three conferred a slight increase in fitness. In contrast, mutations conferring CTL escape in the p24 epitopes significantly decreased viral fitness. One particular escape mutation within a p24 epitope was associated with reduced peptide recognition and high viral fitness costs but was replaced by a fitness-neutral mutation. This mutation appeared to alter epitope processing concomitant with a reduced CTL response. In conclusion, CTL escape mutations in HIV-1 Gag p24 were associated with significant fitness costs, whereas most escape mutations in the Env gene were fitness neutral, suggesting a balance between immunologic escape and replicative fitness costs

Iatrogenic air embolism: pathoanatomy, thromboinflammation, endotheliopathy, and therapies

Iatrogenic vascular air embolism is a relatively infrequent event but is associated with significant morbidity and mortality. These emboli can arise in many clinical settings such as neurosurgery, cardiac surgery, and liver transplantation, but more recently, endoscopy, hemodialysis, thoracentesis, tissue biopsy, angiography, and central and peripheral venous access and removal have overtaken surgery and trauma as significant causes of vascular air embolism. The true incidence may be greater since many of these air emboli are asymptomatic and frequently go undiagnosed or unreported. Due to the rarity of vascular air embolism and because of the many manifestations, diagnoses can be difficult and require immediate therapeutic intervention. An iatrogenic air embolism can result in both venous and arterial emboli whose anatomic locations dictate the clinical course. Most clinically significant iatrogenic air emboli are caused by arterial obstruction of small vessels because the pulmonary gas exchange filters the more frequent, smaller volume bubbles that gain access to the venous circulation. However, there is a subset of patients with venous air emboli caused by larger volumes of air who present with more protean manifestations. There have been significant gains in the understanding of the interactions of fluid dynamics, hemostasis, and inflammation caused by air emboli due to in vitro and in vivo studies on flow dynamics of bubbles in small vessels. Intensive research regarding the thromboinflammatory changes at the level of the endothelium has been described recently. The obstruction of vessels by air emboli causes immediate pathoanatomic and immunologic and thromboinflammatory responses at the level of the endothelium. In this review, we describe those immunologic and thromboinflammatory responses at the level of the endothelium as well as evaluate traditional and novel forms of therapy for this rare and often unrecognized clinical condition

Daily Sampling of an HIV-1 Patient with Slowly Progressing Disease Displays Persistence of Multiple env Subpopulations Consistent with Neutrality

The molecular evolution of HIV-1 is characterized by frequent substitutions, indels and recombination events. In addition, a HIV-1 population may adapt through frequency changes of its variants. To reveal such population dynamics we analyzed HIV-1 subpopulation frequencies in an untreated patient with stable, low plasma HIV-1 RNA levels and close to normal CD4+ T-cell levels. The patient was intensively sampled during a 32-day period as well as approximately 1.5 years before and after this period (days −664, 1, 2, 3, 11, 18, 25, 32 and 522). 77 sequences of HIV-1 env (approximately 3100 nucleotides) were obtained from plasma by limiting dilution with 7–11 sequences per time point, except day −664. Phylogenetic analysis using maximum likelihood methods showed that the sequences clustered in six distinct subpopulations. We devised a method that took into account the relatively coarse sampling of the population. Data from days 1 through 32 were consistent with constant within-patient subpopulation frequencies. However, over longer time periods, i.e. between days 1…32 and 522, there were significant changes in subpopulation frequencies, which were consistent with evolutionarily neutral fluctuations. We found no clear signal of natural selection within the subpopulations over the study period, but positive selection was evident on the long branches that connected the subpopulations, which corresponds to >3 years as the subpopulations already were established when we started the study. Thus, selective forces may have been involved when the subpopulations were established. Genetic drift within subpopulations caused by de novo substitutions could be resolved after approximately one month. Overall, we conclude that subpopulation frequencies within this patient changed significantly over a time period of 1.5 years, but that this does not imply directional or balancing selection. We show that the short-term evolution we study here is likely representative for many patients of slow and normal disease progression