Unifying viral evolution and immunological patterns to investigate risk of HIV-1 disease progression

After 30 years of research, the exact mechanisms underlying human immunodeficiency virus type 1 (HIV-1) pathogenesis and disease progression remain elusive. In the absence of highly active antiretroviral therapy, most HIV-infected individuals progress to AIDS within 10 years. The clinical course of HIV-1 infection is characterized by considerable variability in the rate of disease progression among patients with different genetic background. It has been shown that the rate of progression can depend on the expression of certain human leukocyte antigen (HLA) class I alleles that present antigen to the host immune system. The HLA-B*5701 allele is most strongly associated with slower progression. Underlying mechanisms are not fully understood but likely involve both immunological and virological dynamics. In this thesis, viral evolution and immunological patterns were studied in the context of HIV-1 risk of disease progression in HLA-B*5701 subjects and non-HLA-B*57 control subjects. First, HIV-1 in vivo evolution and epitope-specific CD8+ T cell responses were investigated in six untreated HLA-B*5701 patients monitored from early infection up to seven years post-infection. The subjects were classified as high-risk progressors (HRPs) or low-risk progressors (LRPs) based on viral load and baseline CD4+ T cell counts. Interestingly, polyfunctional CD8+ T cell responses were more robust in LRPs, who also showed significantly higher interleukin-2 production in early infection compared to HRPs. Additionally, HIV-1 gag p24 sequences exhibited more constrained mutational patterns with significantly lower diversity and intra-host evolutionary rates in LRPs than HRPs. Further in-depth analyses revealed that the difference in evolutionary rates was mainly due to significantly lower HIV-1 synonymous substitution [replication] rates in LRPs than HRPs. The viral quasispecies infecting LRPs was also characterized by a slower increase in synonymous divergence over time. This pattern did not correlate to differences in viral fitness, as measured by in vitro replication capacity, but a significant inverse correlation between baseline CD4+ T cell counts and mean HIV-1 synonymous rate was found. The results indicate that HLAlinked immune responses in HLA-B*5701 subjects who maintain high CD4+ T cell counts in early infection are more likely to control HIV-1 replication for an extended time. To further assess these findings and evaluate them in the context of viral population dynamics, a new method was implemented to investigate the temporal structure of phylogenetic trees inferred from HIV-1 intra-host longitudinal samples. The analysis revealed that changes in viral effective population size (Ne) over time were more constrained in HLA-B*5701 subjects compared to non-HLA-B*57 controls, possibly due to the different evolutionary dynamics of archival viral strains observed in the two groups of patients. Explaining the differences in risk of HIV-1 disease progression among HLAB* 5701 subjects, as well as between HLA-B*5701 and non-HLA-B*57 subjects, could have significant translational impact by providing specific correlates of protection that are essential for the successful development of a vaccine. Ultimately, the present work demonstrates that a thorough understanding of HIV-1 pathogenesis and disease progression requires a multidisciplinary approach unifying viral evolution and immunological patterns

PhyloTempo: A Set of R Scripts for Assessing and Visualizing Temporal Clustering in Genealogies Inferred from Serially Sampled Viral Sequences

Serially-sampled nucleotide sequences can be used to infer demographic history of evolving viral populations. The shape of a phylogenetic tree often reflects the interplay between evolutionary and ecological processes. Several approaches exist to analyze the topology and traits of a phylogenetic tree, by means of tree balance, branching patterns and comparative properties. The temporal clustering (TC) statistic is a new topological measure, based on ancestral character reconstruction, which characterizes the temporal structure of a phylogeny. Here, PhyloTempo is the first implementation of the TC in the R language, integrating several other topological measures in a user-friendly graphical framework. The comparison of the TC statistic with other measures provides multifaceted insights on the dynamic processes shaping the evolution of pathogenic viruses. The features and applicability of PhyloTempo were tested on serially-sampled intra-host human and simian immunodeficiency virus population data sets. PhyloTempo is distributed under the GNU general public license at https://sourceforge.net/projects/phylotempo/

Capturing systematically users' experience of evaluation tools for integrated AMU and AMR surveillance

Tackling antimicrobial resistance (AMR) is a goal for many countries. Integrated surveillance of antimicrobial use (AMU) and resistance is a prerequisite for effective risk mitigation. Regular evaluation of any surveillance is needed to ensure its effectiveness and efficiency. The question is how to evaluate specifically integrated surveillance for AMU and AMR. In an international network called CoEvalAMR, we have developed guidelines for selection of the most appropriate tools for such an evaluation. Moreover, we have assessed different evaluation tools as examples using a country case format and a methodology with a focus on the user's experience. This paper describes the updated methodology, which consists of a brief introduction to the case and to the tool separately. Moreover, there are 12 functional aspects and nine content themes which should be scored using a 4-tiered scale. Additionally, four Strengths, Weaknesses, Opportunities, Threats (SWOT) questions should be addressed. Results are illustrated using radar diagrams. An example of application of the updated methodology is given using the ECoSur evaluation tool. No tool can cover all evaluation aspects comprehensively in a user-friendly manner, so the choice of tool must be based upon the specific evaluation purpose. Moreover, adequate resources, time and training are needed to obtain useful outputs from the evaluation. Our updated methodology can be used by tool users to share their experience with available tools, and hereby assist other users in identifying the most suited tool for their evaluation purpose. Additionally, tool developers can get valuable information for further improvements of their tool

Estimating the public health impact of disbanding a government alcohol monopoly: Application of new methods to the case of Sweden

Background: Government alcohol monopolies were created in North America and Scandinavia to limit health and social problems. The Swedish monopoly, Systembolaget, reports to a health ministry and controls the sale of all alcoholic beverages with > 3.5% alcohol/volume for off-premise consumption, within a public health mandate. Elsewhere, alcohol monopolies are being dismantled with evidence of increased consumption and harms. We describe innovative modelling techniques to estimate health outcomes in scenarios involving Systembolaget being replaced by 1) privately owned liquor stores, or 2) alcohol sales in grocery stores. The methods employed can be applied in other jurisdictions and for other policy changes. Methods: Impacts of the privatisation scenarios on pricing, outlet density, trading hours, advertising and marketing were estimated based on Swedish expert opinion and published evidence. Systematic reviews were conducted to estimate impacts on alcohol consumption in each scenario. Two methods were applied to estimate harm impacts: (i) alcohol attributable morbidity and mortality were estimated utilising the International Model of Alcohol Harms and Policies (InterMAHP); (ii) ARIMA methods to estimate the relationship between per capita alcohol consumption and specific types of alcohol-related mortality and crime. Results: Replacing government stores with private liquor stores (Scenario 1) led to a 20.0% (95% CI, 15.3-24.7) increase in per capita consumption. Replacement with grocery stores (Scenario 2) led to a 31.2% (25.1-37.3%) increase. With InterMAHP there were 763 or + 47% (35-59%) and 1234 or + 76% (60-92%) more deaths per year, for Scenarios 1 and 2 respectively. With ARIMA, there were 850 (334-1444) more deaths per year in Scenario 1 and 1418 more in Scenario 2 (543-2505). InterMAHP also estimated 10,859 or + 29% (22-34%) and 16,118 or + 42% (35-49%) additional hospital stays per year respectively. Conclusions: There would be substantial adverse consequences for public health and safety were Systembolaget to be privatised. We demonstrate a new combined approach for estimating the impact of alcohol policies on consumption and, using two alternative methods, alcohol-attributable harm. This approach could be readily adapted to other policies and settings. We note the limitation that some significant sources of uncertainty in the estimates of harm impacts were not modelled

Reduction of the HIV-1 reservoir in resting CD4+ T-lymphocytes by high dosage intravenous immunoglobulin treatment: a proof-of-concept study

<p>Abstract</p> <p>Background</p> <p>The latency of HIV-1 in resting CD4⁺T-lymphocytes constitutes a major obstacle for the eradication of virus in patients on antiretroviral therapy (ART). As yet, no approach to reduce this viral reservoir has proven effective.</p> <p>Methods</p> <p>Nine subjects on effective ART were included in the study and treated with high dosage intravenous immunoglobulin (IVIG) for five consecutive days. Seven of those had detectable levels of replication-competent virus in the latent reservoir and were thus possible to evaluate. Highly purified resting memory CD4⁺T-cells were activated and cells containing replication-competent HIV-1 were quantified. HIV-1 from plasma and activated memory CD4⁺T-cells were compared with single genome sequencing (SGS) of the <it>gag </it>region. T-lymphocyte activation markers and serum interleukins were measured.</p> <p>Results</p> <p>The latent HIV-1 pool decreased with in median 68% after IVIG was added to effective ART. The reservoir decreased in five, whereas no decrease was found in two subjects with detectable virus. Plasma HIV-1 RNA ≥ 2 copies/mL was detected in five of seven subjects at baseline, but in only one at follow-up after 8–12 weeks. The decrease of the latent HIV-1 pool and the residual plasma viremia was preceded by a transitory low-level increase in plasma HIV-1 RNA and serum interleukin 7 (IL-7) levels, and followed by an expansion of T regulatory cells. The magnitude of the viral increase in plasma correlated to the size of the latent HIV-1 pool and SGS of the <it>gag </it>region showed that viral clones from plasma clustered together with virus from activated memory T-cells, pointing to the latent reservoir as the source of HIV-1 RNA in plasma.</p> <p>Conclusion</p> <p>The findings from this uncontrolled proof-of-concept study suggest that the reservoir became accessible by IVIG treatment through activation of HIV-1 gene expression in latently-infected resting CD4⁺T-cells. We propose that IVIG should be further evaluated as an adjuvant to effective ART.</p

Seeds of good anthropocenes: developing sustainability scenarios for Northern Europe

Scenario development helps people think about a broad variety of possible futures; however, the global environmental change community has thus far developed few positive scenarios for the future of the planet and humanity. Those that have been developed tend to focus on the role of a few common, large-scale external drivers, such as technology or environmental policy, even though pathways of positive change are often driven by surprising or bottom-up initiatives that most scenarios assume are unchanging. We describe an approach, pioneered in Southern Africa and tested here in a new context in Northern Europe, to developing scenarios using existing bottom-up transformative initiatives to examine plausible transitions towards positive, sustainable futures. By starting from existing, but marginal initiatives, as well as current trends, we were able to identify system characteristics that may play a key role in sustainability transitions (e.g., gender issues, inequity, governance, behavioral change) that are currently under-explored in global environmental scenarios. We suggest that this approach could be applied in other places to experiment further with the methodology and its potential applications, and to explore what transitions to desirables futures might be like in different places

Co-production of knowledge and sustainability transformations: a strategic compass for global research networks

An increasing number of voices highlight the need for science itself to transform and to engage in the co-production of knowledge and action, in order to enable the fundamental transformations needed to advance towards sustainable futures. But how can global sustainability-oriented research networks engage in co-production of knowledge and action? The present article introduces a strategic tool called the ‘network compass’ which highlights four generic, interrelated fields of action through which networks can strive to foster co-production. It is based on the networks’ particular functions and how these can be engaged for co-production processes. This tool aims to foster self-reflection and learning within and between networks in the process of (re)developing strategies and activity plans and effectively contributing to sustainability transformations

Combining fish and benthic communities into multiple regimes reveals complex reef dynamics

Abstract Coral reefs worldwide face an uncertain future with many reefs reported to transition from being dominated by corals to macroalgae. However, given the complexity and diversity of the ecosystem, research on how regimes vary spatially and temporally is needed. Reef regimes are most often characterised by their benthic components; however, complex dynamics are associated with losses and gains in both fish and benthic assemblages. To capture this complexity, we synthesised 3,345 surveys from Hawai‘i to define reef regimes in terms of both fish and benthic assemblages. Model-based clustering revealed five distinct regimes that varied ecologically, and were spatially heterogeneous by island, depth and exposure. We identified a regime characteristic of a degraded state with low coral cover and fish biomass, one that had low coral but high fish biomass, as well as three other regimes that varied significantly in their ecology but were previously considered a single coral dominated regime. Analyses of time series data reflected complex system dynamics, with multiple transitions among regimes that were a function of both local and global stressors. Coupling fish and benthic communities into reef regimes to capture complex dynamics holds promise for monitoring reef change and guiding ecosystem-based management of coral reefs