Untargeted Metabolite Profile Associations with Body Mass Index, Waist-Hip Ratio, and Antiretroviral Therapy in >1300 People with HIV: the Swiss HIV Cohort Study.

Background: Obesity is a major concern in people with HIV (PWH). How obesity and antiretroviral therapy (ART) are associated with specific metabolite profiles in PWH is not well described.

Methods: We included Swiss HIV Cohort Study participants aged ≥45 years.

HIV-phyloTSI: subtype-independent estimation of time since HIV-1 infection for cross-sectional measures of population incidence using deep sequence data.

Background: Estimating the time since HIV infection (TSI) at population level is essential for tracking changes in the global HIV epidemic. Most methods for determining TSI give a binary classification of infections as recent or non-recent within a window of several months, and cannot assess the cumulative impact of an intervention.

Results: We developed a Random Forest Regression model, HIV-phyloTSI, which combines measures of within-host diversity and divergence to generate continuous TSI estimates directly from viral deep-sequencing data, with no need for additional variables.

Structure-based metabolite function prediction using graph neural networks.

Motivation: Being able to broadly predict the function of novel metabolites based on their structures has applications in systems biology, environmental monitoring, and drug discovery. To date, machine learning models aiming to predict functional characteristics of metabolites have largely been limited in scope to predicting single functions, or only a small number of functions simultaneously.

Results: Using the Human Metabolome Database as a source for a wider range of functional annotations, we assess the feasibility of predicting metabolite functions more broadly, as defined by four elements, namely location, role, the process it is involved in, and its physiological effect.

Granulysin Antimicrobial Activity Promotes Dormancy in Mycobacterium tuberculosis.

Human tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) remains a global public health threat. Granulomas constitute a hallmark of TB pathogenesis that can clear, contain, or exacerbate an infection. Containment is exploited by Mtb as a hideout to persist in a dormant, antibiotic-tolerant state, only to resuscitate upon immunosuppression.

Leukocyte count and new-onset diabetes mellitus in people with HIV: A longitudinal study.

Objectives: The risk of diabetes mellitus (DM) is increased in people with HIV. Chronic inflammation contributes to DM risk. High leukocytes are associated with DM in the general population, but in people with HIV, evidence of a leukocyte-DM association is limited.

Types of Myocardial Infarction in People With HIV in Switzerland.

Background: Of myocardial infarctions (MIs) recorded in 2 large human immunodeficiency virus (HIV) observational studies from North America, approximately half were classified as type 2. In the REPRIEVE clinical trial of pitavastatin versus placebo in people with HIV (PWH) (<3% of participants were from Europe), 20.6% of MIs were type 2.

Low Trauma Fractures in People with HIV: Longitudinal Time Trends in the Swiss HIV Cohort Study 2009-2022.

Background: People with HIV are at increased risk of low trauma fractures (LTFs). Published data on LTF incidence trends over time has not been uniform. This study sought to analyze LTF time trends in the Swiss HIV Cohort Study (SHCS) 2009-2022.

Proteome-wide prediction of the mode of inheritance and molecular mechanisms underlying genetic diseases using structural interactomics.

Genetic diseases can be classified according to their modes of inheritance and their underlying molecular mechanisms. Autosomal dominant disorders often result from DNA variants that cause loss-of-function, gain-of-function, or dominant-negative effects, while autosomal recessive diseases are primarily linked to loss-of-function variants. In this study, we introduce a graph-of-graphs approach that leverages protein-protein interaction networks and high-resolution protein structures to predict the mode of inheritance of diseases caused by variants in autosomal genes and to classify dominant-associated proteins based on their functional effect.

Decoding the interactions and functions of non-coding RNA with artificial intelligence.

In addition to encoding proteins, mRNAs have context-specific regulatory roles that contribute to many cellular processes. However, uncovering new mRNA functions is constrained by limitations of traditional biochemical and computational methods. In this Roadmap, we highlight how artificial intelligence can transform our understanding of RNA biology by fostering collaborations between RNA biologists and computational scientists to drive innovation in this fundamental field of research.

Fine-tuning protein language models to understand the functional impact of missense variants.

Elucidating the functional effects of missense variants is crucial yet challenging. To investigate their impact, we fine-tuned protein language models, including ESM2 and ProtT5, to classify 20 protein features at amino acid resolution. In addition, we trained a fully connected neural network classifier on frozen embeddings and compared its performance to fine-tuning in order to quantify the added value of task-specific adaptation.

Polygenic Risk Scores for Type 2 Diabetes in the Swiss HIV Cohort Study.

Background: Type 2 diabetes (T2D) is among the most frequent comorbidities in people with HIV (PWH) and occurs more often in PWH than in people without HIV. Polygenic risk scores (PRS) can be used to summarize the genetic risk for T2D, but it is unknown to what extent HIV-specific factors impact on or interact with genetic risk factors.

Methods: We performed a case control study using incidence density sampling to match participants with T2D to controls within the Swiss HIV Cohort Study (mean age 51.

Genome-to-genome analysis reveals associations between human and mycobacterial genetic variation in tuberculosis patients from Tanzania.

The risk and prognosis of tuberculosis (TB) are influenced by a complex interplay between human and bacterial genetic factors. While previous genomic studies have largely examined human and bacterial genomes separately, we adopted an integrated approach to uncover host-pathogen interactions. We leveraged paired human and Mycobacterium tuberculosis (M.

Enhanced TLR7-dependent production of type I interferon by pDCs underlies pandemic chilblains.

Outbreaks of chilblains were reported during the COVID-19 pandemic. Given the essential role of type I interferon (I-IFN) in protective immunity against SARS-CoV-2 and the association of chilblains with inherited type I interferonopathies, we hypothesized that excessive I-IFN responses to SARS-CoV-2 might underlie the occurrence of chilblains in this context. We identified a transient I-IFN signature in chilblain lesions, accompanied by an acral infiltration of activated plasmacytoid dendritic cells (pDCs).

Deciphering the Foundations of Mitochondrial Mutational Spectra: Replication-Driven and Damage-Induced Signatures Across Chordate Classes.

Mitochondrial DNA (mtDNA) mutagenesis remains poorly understood despite its crucial role in disease, aging, and evolutionary tracing. In this study, we reconstructed a comprehensive 192-component mtDNA mutational spectrum for chordates by analyzing 118,397 synonymous mutations in the CytB gene across 1,697 species and five classes. This analysis revealed three primary forces shaping mtDNA mutagenesis: (i) symmetrical, replication-driven errors by mitochondrial polymerase (POLG), resulting in C > T and A > G mutations that are highly conserved across classes; (ii) asymmetrical, damage-driven C > T mutations on the single-stranded heavy strand with clock-like dynamics; and (iii) asymmetrical A > G mutations on the heavy strand, with dynamics suggesting sensitivity to oxidative damage.

Paediatric Personalized Research Network Switzerland (SwissPedHealth): a joint paediatric national data stream.

Introduction: Children represent a large and vulnerable patient group. However, the evidence base for most paediatric diagnostic and therapeutic procedures remains limited or is often inferred from adults. There is an urgency to improve paediatric healthcare provision based on real-world evidence generation.

EBNA-1 and VCA-p18 immunoglobulin markers link Epstein-Barr virus immune response and brain's myelin content to fatigue in a community-dwelling cohort.

Given the association of Epstein-Barr virus (EBV) with subjective perception of fatigue and demyelination in clinical conditions, the question about potential subclinical effects in the adult general population remains open. We investigate the association between individuals' EBV immune response and perceived fatigue in a community dwelling cohort (n = 864, age 62 ± 10 years old; 49% women) while monitoring brain tissue properties. Fatigue levels are assessed with the established fatigue severity scale, the EBNA-1 and VCA p18 immunoglobulin G (IgG) chronic response - with multiplex serology and the estimates of local brain volume, myelin content, and axonal density - using relaxometry- and multi-shell diffusion-based magnetic resonance imaging (MRI).

Using viral diversity to identify HIV-1 variants under HLA-dependent selection in a systematic viral genome-wide screen.

The pathogenesis of HIV-1 infection is governed by a highly dynamic, time-dependent interaction between the host and the viral genome. In this study, we developed a novel systematic approach to assess the host-virus interaction, using average pairwise viral diversity as a proxy for time since infection, and applied this method to nearly whole viral genome sequences (n = 4,464), human leukocyte antigen (HLA) genotyping data (n = 1,044), and viral RNA load (VL) measurements during the untreated chronic phase (n = 829) of Swiss HIV Cohort Study participants. Our systematic genome-wide screen revealed for 98 HLA/viral-variant pairs a signature of immune-driven selection in the form of an HLA-dependent effect of infection time on the presence of HIV amino acid variants.

Loss of tolerance precedes triggering and lifelong persistence of pathogenic type I interferon autoantibodies.

Autoantibodies neutralizing type I interferons (IFN-Is) can underlie infection severity. Here, we trace the development of these autoantibodies at high-resolution using longitudinal samples from 1,876 well-treated individuals living with HIV over a 35-year period. Similar to general populations, ∼1.

Epistatic interaction between ERAP2 and HLA modulates HIV-1 adaptation and disease outcome in an Australian population.

A strong genetic predictor of outcome following untreated HIV-1 infection is the carriage of specific alleles of human leukocyte antigens (HLAs) that present viral epitopes to T cells. Residual variation in outcome measures may be attributed, in part, to viral adaptation to HLA-restricted T cell responses. Variants of the endoplasmic reticulum aminopeptidases (ERAPs) influence the repertoire of T cell epitopes presented by HLA alleles as they trim pathogen-derived peptide precursors to optimal lengths for antigen presentation, along with other functions unrelated to antigen presentation.

Self-reported neurocognitive complaints in the Swiss HIV Cohort Study: a viral genome-wide association study.

People with HIV may report neurocognitive complaints, with or without associated neurocognitive impairment, varying between individuals and populations. While the HIV genome could play a major role, large systematic viral genome-wide screens to date are lacking. The Swiss HIV Cohort Study biannually enquires neurocognitive complaints.

Joint host-pathogen genomic analysis identifies hepatitis B virus mutations associated with human NTCP and HLA class I variation.

Evolutionary changes in the hepatitis B virus (HBV) genome could reflect its adaptation to host-induced selective pressure. Leveraging paired human exome and ultra-deep HBV genome-sequencing data from 567 affected individuals with chronic hepatitis B, we comprehensively searched for the signatures of this evolutionary process by conducting "genome-to-genome" association tests between all human genetic variants and viral mutations. We identified significant associations between an East Asian-specific missense variant in the gene encoding the HBV entry receptor NTCP (rs2296651, NTCP S267F) and mutations within the receptor-binding region of HBV preS1.

Diagnostic accuracy of a sequence-specific -DNA hybridization assay in urine: a case-control study including subclinical TB cases.

Unlabelled: Tuberculosis (TB) caused by () remains one of the deadliest infectious diseases globally. Timely diagnosis is a key step in the management of TB patients and in the prevention of further transmission events. Current diagnostic tools are limited in these regards.

Lack of association between classical HLA genes and asymptomatic SARS-CoV-2 infection.

Human genetic studies of critical COVID-19 pneumonia have revealed the essential role of type I interferon-dependent innate immunity to SARS-CoV-2 infection. Conversely, an association between the HLA-B∗15:01 allele and asymptomatic SARS-CoV-2 infection in unvaccinated individuals was recently reported, suggesting a contribution of pre-existing T cell-dependent adaptive immunity. We report a lack of association of classical HLA alleles, including HLA-B∗15:01, with pre-omicron asymptomatic SARS-CoV-2 infection in unvaccinated participants in a prospective population-based study in the United States (191 asymptomatic vs.

Bacterial diversity dominates variable macrophage responses of tuberculosis patients in Tanzania.

The Mycobacterium tuberculosis complex (MTBC) comprises nine human-adapted lineages that differ in their geographical distribution. Local adaptation of specific MTBC genotypes to the respective human host population has been invoked in this context. We aimed to assess if bacterial genetics governs MTBC pathogenesis or if local co-adaptation translates into differential susceptibility of human macrophages to infection by different MTBC genotypes.