Tenofovir treatment augments anti-viral immunity against drug-resistant SIV challenge in chronically infected rhesus macaques

BACKGROUND: Emergence of drug-resistant strains of human immunodeficiency virus type 1 (HIV-1) is a major obstacle to successful antiretroviral therapy (ART) in HIV-infected patients. Whether antiviral immunity can augment ART by suppressing replication of drug-resistant HIV-1 in humans is not well understood, but can be explored in non-human primates infected with simian immunodeficiency virus (SIV). Rhesus macaques infected with live, attenuated SIV develop robust SIV-specific immune responses but remain viremic, often at low levels, for periods of months to years, thus providing a model in which to evaluate the contribution of antiviral immunity to drug efficacy. To investigate the extent to which SIV-specific immune responses augment suppression of drug-resistant SIV, rhesus macaques infected with live, attenuated SIVmac239Δnef were treated with the reverse transcriptase (RT) inhibitor tenofovir, and then challenged with pathogenic SIVmac055, which has a five-fold reduced sensitivity to tenofovir. RESULTS: Replication of SIVmac055 was detected in untreated macaques infected with SIVmac239Δnef, and in tenofovir-treated, naïve control macaques. The majority of macaques infected with SIVmac055 experienced high levels of plasma viremia, rapid CD4(+ )T cell loss and clinical disease progression. By comparison, macaques infected with SIVmac239Δnef and treated with tenofovir showed no evidence of replicating SIVmac055 in plasma using allele-specific real-time PCR assays with a limit of sensitivity of 50 SIV RNA copies/ml plasma. These animals remained clinically healthy with stable CD4(+ )T cell counts during three years of follow-up. Both the tenofovir-treated and untreated macaques infected with SIVmac239Δnef had antibody responses to SIV gp130 and p27 antigens and SIV-specific CD8(+ )T cell responses prior to SIVmac055 challenge, but only those animals receiving concurrent treatment with tenofovir resisted infection with SIVmac055. CONCLUSION: These results support the concept that anti-viral immunity acts synergistically with ART to augment drug efficacy by suppressing replication of viral variants with reduced drug sensitivity. Treatment strategies that seek to combine immunotherapeutic intervention as an adjunct to antiretroviral drugs may therefore confer added benefit by controlling replication of HIV-1, and reducing the likelihood of treatment failure due to the emergence of drug-resistant virus, thereby preserving treatment options

Efficient multiscale imaging of subsurface resistivity with uncertainty quantification using ensemble Kalman inversion

Electrical resistivity tomography (ERT) is widely used to image the Earth's subsurface and has proven to be an extremely useful tool in application to hydrological problems. Conventional smoothness-constrained inversion of ERT data is efficient and robust, and consequently very popular. However, it does not resolve well sharp interfaces of a resistivity field and tends to reduce and smooth resistivity variations. These issues can be problematic in a range of hydrological or near-surface studies, for example mapping regolith-bedrock interfaces. While fully Bayesian approaches, such as those using Markov chain Monte Carlo sampling, can address the above issues, their very high computation cost makes them impractical for many applications. Ensemble Kalman inversion (EKI) offers a computationally efficient alternative by approximating the Bayesian posterior distribution in a derivative-free manner, which means only a relatively small number of 'black-box' model runs are required. Although common limitations for ensemble Kalman filter-type methods apply to EKI, it is both efficient and generally captures uncertainty patterns correctly. We propose the use of a new EKI-based framework for ERT which estimates a resistivity model and its uncertainty at a modest computational cost. Our EKI framework uses a level-set parametrization of the unknown resistivity to allow efficient estimation of discontinuous resistivity fields. Instead of estimating level-set parameters directly, we introduce a second step to characterize the spatial variability of the resistivity field and infer length scale hyperparameters directly. We demonstrate these features by applying the method to a series of synthetic and field examples. We also benchmark our results by comparing them to those obtained from standard smoothness-constrained inversion. Resultant resistivity images from EKI successfully capture arbitrarily shaped interfaces between resistivity zones and the inverted resistivities are close to the true values in synthetic cases. We highlight its readiness and applicability to similar problems in geophysics

Time-lapse geophysical assessment of agricultural practices on soil moisture dynamics

Geophysical surveys are now commonly used in agriculture for mapping applications. High-throughput collection of geophysical properties such as electrical conductivity (inverse of resistivity), can be used as a proxy for soil properties of interest (e.g. moisture, texture, salinity). Most applications only rely on a single geophysical survey at a given time. However, time-lapse geophysical surveys have greater capabilities to characterize the dynamics of the system, which is the focus of this work. Assessing the impact of agricultural practices through the growth season can reveal important information for the crop production. In this work, we demonstrate the use of time-lapse electrical resistivity tomography (ERT) and electromagnetic induction (EMI) surveys through a series of three case studies illustrating common agricultural practices (cover crops, compaction with irrigation, tillage with nitrogen fertilization). In the first case study, time-lapse EMI reveals the initial effect of cover crops on soil drying and the absence of effect on the subsequent main crop. In the second case study, compaction, leading to a shallower drying depth for potatoes was imaged by time-lapse ERT. In the third case study, larger change in electrical conductivity over time were observed in conventional tillage compared to direct drill using time-lapse EMI. In addition, different nitrogen application rates had significant effect on the yield and leaf area index but only ephemeral effects on the dynamics of electrical conductivity mainly after the first application. Overall, time-lapse geophysical surveys show great potential for monitoring the impact of different agricultural practices that can influence crop yield

A novel grass hybrid to reduce flood generation in temperate regions

We report on the evaluation of a novel grass hybrid that provides efficient forage production and could help mitigate flooding. Perennial ryegrass (Lolium perenne) is the grass species of choice for most farmers, but lacks resilience against extremes of climate. We hybridised L. perenne onto a closely related and more stress-resistant grass species, meadow fescue Festuca pratensis. We demonstrate that the L. perenne × F. pratensis cultivar can reduce runoff during the events by 51% compared to a leading UK nationally recommended L. perenne cultivar and by 43% compared to F. pratensis over a two year field experiment. We present evidence that the reduced runoff from this Festulolium cultivar was due to intense initial root growth followed by rapid senescence, especially at depth. Hybrid grasses of this type show potential for reducing the likelihood of flooding, whilst providing food production under conditions of changing climate

Image informatics strategies for deciphering neuronal network connectivity

Brain function relies on an intricate network of highly dynamic neuronal connections that rewires dramatically under the impulse of various external cues and pathological conditions. Among the neuronal structures that show morphologi- cal plasticity are neurites, synapses, dendritic spines and even nuclei. This structural remodelling is directly connected with functional changes such as intercellular com- munication and the associated calcium-bursting behaviour. In vitro cultured neu- ronal networks are valuable models for studying these morpho-functional changes. Owing to the automation and standardisation of both image acquisition and image analysis, it has become possible to extract statistically relevant readout from such networks. Here, we focus on the current state-of-the-art in image informatics that enables quantitative microscopic interrogation of neuronal networks. We describe the major correlates of neuronal connectivity and present workflows for analysing them. Finally, we provide an outlook on the challenges that remain to be addressed, and discuss how imaging algorithms can be extended beyond in vitro imaging studies

Fine-Scale in Situ Measurement of Riverbed Nitrate Production and Consumption in an Armored Permeable Riverbed

Alteration of the global nitrogen cycle by man has increased nitrogen loading in waterways considerably, often with harmful consequences for aquatic ecosystems. Dynamic redox conditions within riverbeds support a variety of nitrogen transformations, some of which can attenuate this burden. In reality, however, assessing the importance of processes besides perhaps denitrification is difficult, due to a sparseness of data, especially in situ, where sediment structure and hydrologic pathways are intact. Here we show in situ within a permeable riverbed, through injections of 15N-labeled substrates, that nitrate can be either consumed through denitrification or produced through nitrification, at a previously unresolved fine (centimeter) scale. Nitrification and denitrification occupy different niches in the riverbed, with denitrification occurring across a broad chemical gradient while nitrification is restricted to more oxic sediments. The narrow niche width for nitrification is in effect a break point, with the switch from activity “on” to activity “off” regulated by interactions between subsurface chemistry and hydrology. Although maxima for denitrification and nitrification occur at opposing ends of a chemical gradient, high potentials for both nitrate production and consumption can overlap when groundwater upwelling is strong

Hyperresolution information and hyperresolution ignorance in modelling the hydrology of the land surface

There is a strong drive towards hyperresolution earth system models in order to resolve finer scales of motion in the atmosphere. The problem of obtaining more realistic representation of terrestrial fluxes of heat and water, however, is not just a problem of moving to hyperresolution grid scales. It is much more a question of a lack of knowledge about the parameterisation of processes at whatever grid scale is being used for a wider modelling problem. Hyperresolution grid scales cannot alone solve the problem of this hyperresolution ignorance. This paper discusses these issues in more detail with specific reference to land surface parameterisations and flood inundation models. The importance of making local hyperresolution model predictions available for evaluation by local stakeholders is stressed. It is expected that this will be a major driving force for improving model performance in the future. Keith BEVEN, Hannah CLOKE, Florian PAPPENBERGER, Rob LAMB, Neil HUNTE

Characteristics of the Earliest Cross-Neutralizing Antibody Response to HIV-1

Recent cross-sectional analyses of HIV-1+ plasmas have indicated that broadly cross-reactive neutralizing antibody responses are developed by 10%–30% of HIV-1+ subjects. The timing of the initial development of such anti-viral responses is unknown. It is also unknown whether the emergence of these responses coincides with the appearance of antibody specificities to a single or multiple regions of the viral envelope glycoprotein (Env). Here we analyzed the cross-neutralizing antibody responses in longitudinal plasmas collected soon after and up to seven years after HIV-1 infection. We find that anti-HIV-1 cross-neutralizing antibody responses first become evident on average at 2.5 years and, in rare cases, as early as 1 year following infection. If cross-neutralizing antibody responses do not develop during the first 2–3 years of infection, they most likely will not do so subsequently. Our results indicate a potential link between the development of cross-neutralizing antibody responses and specific activation markers on T cells, and with plasma viremia levels. The earliest cross-neutralizing antibody response targets a limited number of Env regions, primarily the CD4-binding site and epitopes that are not present on monomeric Env, but on the virion-associated trimeric Env form. In contrast, the neutralizing activities of plasmas from subjects that did not develop cross-neutralizing antibody responses target epitopes on monomeric gp120 other than the CD4-BS. Our study provides information that is not only relevant to better understanding the interaction of the human immune system with HIV but may guide the development of effective immunization protocols. Since antibodies to complex epitopes that are present on the virion-associated envelope spike appear to be key components of earliest cross-neutralizing activities of HIV-1+ plasmas, then emphasis should be made to elicit similar antibodies by vaccination