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Rapidly evolving influenza A viruses (IAVs) and influenza B viruses (IBVs) are major causes of recurrent lower respiratory tract infections. Current influenza vaccines elicit antibodies predominantly to the highly variable head region of haemagglutinin and their effectiveness is limited by viral drift1 and suboptimal immune responses2. Here we describe a neuraminidase-targeting monoclonal antibody, FNI9, that potently inhibits the enzymatic activity of all group 1 and group 2 IAVs, as well as Victoria/2/87-like, Yamagata/16/88-like and ancestral IBVs. FNI9 broadly neutralizes seasonal IAVs and IBVs, including the immune-evading H3N2 strains bearing an N-glycan at position 245, and shows synergistic activity when combined with anti-haemagglutinin stem-directed antibodies. Structural analysis reveals that D107 in the FNI9 heavy chain complementarity-determinant region 3 mimics the interaction of the sialic acid carboxyl group with the three highly conserved arginine residues (R118, R292 and R371) of the neuraminidase catalytic site. FNI9 demonstrates potent prophylactic activity against lethal IAV and IBV infections in mice. The unprecedented breadth and potency of the FNI9 monoclonal antibody supports its development for the prevention of influenza illness by seasonal and pandemic viruses.

Memory B cells (MBCs) generate rapid antibody responses upon secondary encounter with a pathogen. Here, we investigated the kinetics, avidity, and cross-reactivity of serum antibodies and MBCs in 155 SARS-CoV-2 infected and vaccinated individuals over a 16-month time frame. SARS-CoV-2-specific MBCs and serum antibodies reached steady-state titers with comparable kinetics in infected and vaccinated individuals. Whereas MBCs of infected individuals targeted both prefusion and postfusion Spike (S), most vaccine-elicited MBCs were specific for prefusion S, consistent with the use of prefusion-stabilized S in mRNA vaccines. Furthermore, a large fraction of MBCs recognizing postfusion S cross-reacted with human betacoronaviruses. The avidity of MBC-derived and serum antibodies increased over time resulting in enhanced resilience to viral escape by SARS-CoV-2 variants, including Omicron BA.1 and BA.2 sublineages, albeit only partially for BA.4 and BA.5 sublineages. Overall, the maturation of high-affinity and broadly reactive MBCs provides the basis for effective recall responses to future SARS-CoV-2 variants., iScience, 26 (1), ISSN:2589-0042

SARS-CoV-2 evolution threatens vaccine- and natural infection-derived immunity as well as the efficacy of therapeutic antibodies. To improve public health preparedness, we sought to predict which existing amino acid mutations in SARS-CoV-2 might contribute to future variants of concern. We tested the predictive value of features comprising epidemiology, evolution, immunology, and neural network-based protein sequence modeling, and identified primary biological drivers of SARS-CoV-2 intra-pandemic evolution. We found evidence that ACE2-mediated transmissibility and resistance to population-level host immunity has waxed and waned as a primary driver of SARS-CoV-2 evolution over time. We retroactively identified with high accuracy (area under the receiver operator characteristic curve, AUROC=0.92-0.97) mutations that will spread, at up to four months in advance, across different phases of the pandemic. The behavior of the model was consistent with a plausible causal structure wherein epidemiological covariates combine the effects of diverse and shifting drivers of viral fitness. We applied our model to forecast mutations that will spread in the future and characterize how these mutations affect the binding of therapeutic antibodies. These findings demonstrate that it is possible to forecast the driver mutations that could appear in emerging SARS-CoV-2 variants of concern. We validate this result against Omicron, showing elevated predictive scores for its component mutations prior to emergence, and rapid score increase across daily forecasts during emergence. This modeling approach may be applied to any rapidly evolving pathogens with sufficiently dense genomic surveillance data, such as influenza, and unknown future pandemic viruses.

Sedimentary successions exposed at basin margins as a result of late-stage inversion, uplift and erosion usually represent only a limited portion of the entire basin fill; thus, they are highly incomplete records of basin evolution. Small satellite basins, however, might have the potential of recording more complete histories. The late Miocene sedimentary history of the Șimleu Basin, a north-eastern satellite of the vast Pannonian Basin, was investigated through the study of large outcrops and correlative well-logs. A full transgressive–regressive cycle is reconstructed, which formed within a ca. 1 million-year time frame (10.6–9.6 Ma). The transgressive phase is represented by coarse-grained deltas overlain by deep-water lacustrine marls. Onset of the regressive phase is indicated by sandy turbidite lobes and channels, followed by slope shales, and topped by stacked deltaic lobes and fluvial deposits. The deep- to shallow-water sedimentary facies are similar to those deposited in the central, deep part of the Pannonian Basin. The Șimleu Basin is thus a close and almost complete outcrop analogue of the Pannonian Basin’s lacustrine sedimentary record known mainly from subsurface data, such as well-logs, cores and seismic sections from the basin interior. This study demonstrates that deposits of small satellite basins may reflect the whole sequence of processes that shaped the major basin, although at a smaller spatial and temporal scale.

The spillovers of betacoronaviruses in humans and the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants highlight the need for broad coronavirus countermeasures. We describe five monoclonal antibodies (mAbs) cross-reacting with the stem helix of multiple betacoronavirus spike glycoproteins isolated from COVID-19 convalescent individuals. Using structural and functional studies, we show that the mAb with the greatest breadth (S2P6) neutralizes pseudotyped viruses from three different subgenera through the inhibition of membrane fusion, and we delineate the molecular basis for its cross-reactivity. S2P6 reduces viral burden in hamsters challenged with SARS-CoV-2 through viral neutralization and Fc-mediated effector functions. Stem helix antibodies are rare, oftentimes of narrow specificity, and can acquire neutralization breadth through somatic mutations. These data provide a framework for structure-guided design of pan-betacoronavirus vaccines eliciting broad protection. ispartof: SCIENCE vol:373 issue:6559 pages:1109-1115 ispartof: location:United States status: published

The recent emergence of SARS-CoV-2 variants of concern1-10 and the recurrent spillovers of coronaviruses11,12 into the human population highlight the need for broadly neutralizing antibodies that are not affected by the ongoing antigenic drift and that can prevent or treat future zoonotic infections. Here we describe a human monoclonal antibody designated S2X259, which recognizes a highly conserved cryptic epitope of the receptor-binding domain and cross-reacts with spikes from all clades of sarbecovirus. S2X259 broadly neutralizes spike-mediated cell entry of SARS-CoV-2, including variants of concern (B.1.1.7, B.1.351, P.1, and B.1.427/B.1.429), as well as a wide spectrum of human and potentially zoonotic sarbecoviruses through inhibition of angiotensin-converting enzyme 2 (ACE2) binding to the receptor-binding domain. Furthermore, deep-mutational scanning and in vitro escape selection experiments demonstrate that S2X259 possesses an escape profile that is limited to a single substitution, G504D. We show that prophylactic and therapeutic administration of S2X259 protects Syrian hamsters (Mesocricetus auratus) against challenge with the prototypic SARS-CoV-2 and the B.1.351 variant of concern, which suggests that this monoclonal antibody is a promising candidate for the prevention and treatment of emergent variants and zoonotic infections. Our data reveal a key antigenic site that is targeted by broadly neutralizing antibodies and will guide the design of vaccines that are effective against all sarbecoviruses.

Background Hospital healthcare workers (HCW), in particular those involved in the clinical care of COVID-19 cases, are presumably exposed to a higher risk of acquiring the disease than the general population. Methods Between April 16 and 30, 2020 we conducted a prospective, SARS-CoV-2 seroprevalence study in HCWs in Southern Switzerland. Participants were hospital personnel with varying COVID-19 exposure risk depending on job function and working site. They provided personal information (including age, sex, occupation, and medical history) and self-reported COVID-19 symptoms. Odds ratio (OR) of seropositivity to IgG antibodies was estimated by univariate and multivariate logistic regressions. Findings Among 4726 participants, IgG antibodies to SARS-CoV-2 were detected in 9.6% of the HCWs. Seropositivity was higher among HCWs working on COVID-19 wards (14.1% (11.9–16.5)) compared to other hospital areas at medium (10.7% (7.6–14.6)) or low risk exposure (7.3% (6.4–8.3)). OR for high vs. medium wards risk exposure was 1.42 (0.91–2.22), P = 0.119, and 1.98 (1.55–2.53), P, The Lancet Regional Health - Europe, 1, ISSN:2666-7762

The repeated spillovers of {beta}-coronaviruses in humans along with the rapid emergence of SARS-CoV-2 escape variants highlight the need to develop broad coronavirus therapeutics and vaccines. Five monoclonal antibodies (mAbs) were isolated from COVID-19 convalescent individuals and found to cross-react with multiple {beta}-coronavirus spike (S) glycoproteins by targeting the stem helix. One of these mAbs, S2P6, cross-reacts with more than twenty human and animal {beta}-coronavirus S glycoproteins and broadly neutralizes SARS-CoV-2 and pseudotyped viruses from the sarbecovirus, merbecovirus and embecovirus subgenera. Structural and functional studies delineate the molecular basis of S2P6 cross-reactivity and broad neutralization and indicate that this mAb blocks viral entry by inhibiting membrane fusion. S2P6 protects hamsters challenged with SARS-CoV-2 (including the B.1.351 variant of concern) through direct viral neutralization and Fc-mediated effector functions. Serological and B cell repertoire analyses indicate that antibodies targeting the stem helix are found in some convalescent donors and vaccinees but are predominantly of narrow specificity. Germline reversion of the identified cross-reactive mAbs revealed that their unmutated ancestors are specific for the endemic OC43 or HKU1 viruses and acquired enhanced affinity and breadth through somatic mutations. These data demonstrate that conserved epitopes in the coronavirus fusion machinery can be targeted by protective antibodies and provide a framework for structure-guided design of pan-{beta}-coronavirus vaccines eliciting broad protection.

Salinization occurs in natural conditions as a result of a complex of factors such as climate, topography, and hydrogeology. Salinity principally occurs in sub-humid to arid regions but secondary salinization is a consequence of direct human activities it extends by the day. In the field, soil salinity is deduced from apparent electrical conductivity (ECa) by using a range of devices. Although a number of proximal sensors have recently been used worldwide to simplify fieldwork, few studies using new technologies have been addressed in Romania. The objective of this study was to assess the spatial variability of the apparent electrical conductivity of saline soils using a DUALEM instrument in Valea Sarata (Cluj). Spatial variability maps were generated by using of a geostatistical method. Significantly higher ECa was detected in poorly drained areas close to water channels (ECa above 1000 mS/m), while lower and less variable ECa values were recorded on the side slopes (ECa.200 mS/m). These areas correspond with eutric salic regosol identified on upper lands. The map of ECa measurements at surface show a higher variability of salinity then at depth at which the ground water disolved the salts. The instrument proved to be more efficient compared with traditional methods, regarding soil salinity mapping and delineating the soil boundaries.

The recent emergence of SARS-CoV-2 variants of concern (VOC) and the recurrent spillovers of coronaviruses in the human population highlight the need for broadly neutralizing antibodies that are not affected by the ongoing antigenic drift and that can prevent or treat future zoonotic infections. Here, we describe a human monoclonal antibody (mAb), designated S2×259, recognizing a highly conserved cryptic receptor-binding domain (RBD) epitope and cross-reacting with spikes from all sarbecovirus clades. S2×259 broadly neutralizes spike-mediated entry of SARS-CoV-2 including the B.1.1.7, B.1.351, P.1 and B.1.427/B.1.429 VOC, as well as a wide spectrum of human and zoonotic sarbecoviruses through inhibition of ACE2 binding to the RBD. Furthermore, deep-mutational scanning and in vitro escape selection experiments demonstrate that S2×259 possesses a remarkably high barrier to the emergence of resistance mutants. We show that prophylactic administration of S2×259 protects Syrian hamsters against challenges with the prototypic SARS-CoV-2 and the B.1.351 variant, suggesting this mAb is a promising candidate for the prevention and treatment of emergent VOC and zoonotic infections. Our data unveil a key antigenic site targeted by broadly-neutralizing antibodies and will guide the design of pan-sarbecovirus vaccines.

Significance Human responses to infection include transcriptional changes shared across diverse pathogens. To capture these common patterns, we establish the concept of, and the method for, the identification of “transfer signatures”: sets of genes defining human immunophenotypes. We demonstrate the usefulness of transfer signatures in two use cases: the progression of latent to active tuberculosis and the severity of viral respiratory infections., The modulation of the transcriptome is among the earliest responses to infection. However, defining the transcriptomic signatures of disease is challenging because logistic, technical, and cost factors limit the size and representativeness of samples in clinical studies. These limitations lead to a poor performance of signatures when applied to new datasets. Although the study focuses on infection, the central hypothesis of the work is the generalization of sets of signatures across diseases. We use a machine learning approach to identify common elements in datasets and then test empirically whether they are informative about a second dataset from a disease or process distinct from the original dataset. We identify sets of genes, which we name transfer signatures, that are predictive across diverse datasets and/or species (e.g., rhesus to humans). We demonstrate the usefulness of transfer signatures in two use cases: the progression of latent to active tuberculosis and the severity of COVID-19 and influenza A H1N1 infection. This indicates that transfer signatures can be deployed in settings that lack disease-specific biomarkers. The broad significance of our work lies in the concept that a small set of archetypal human immunophenotypes, captured by transfer signatures, can explain a larger set of responses to diverse diseases.

Understanding the significance of genetic variants in the noncoding genome is emerging as the next challenge in human genomics. We used the power of 11,257 whole-genome sequences and 16,384 heptamers (7-nt motifs) to build a map of sequence constraint for the human species. This build differed substantially from traditional maps of interspecies conservation and identified regulatory elements among the most constrained regions of the genome. Using new Hi-C experimental data, we describe a strong pattern of coordination over 2 Mb where the most constrained regulatory elements associate with the most essential genes. Constrained regions of the noncoding genome are up to 52-fold enriched for known pathogenic variants as compared to unconstrained regions (21-fold when compared to the genome average). This map of sequence constraint across thousands of individuals is an asset to help interpret noncoding elements in the human genome, prioritize variants and reconsider gene units at a larger scale.

Many hierarchical schemes have been developed to describe multiple-scale cut-and-fill architecture of deep-water channel systems and analyse their evolution. A widely applicable genetical-based scheme is not on the horizon yet. Near seismic-scale exposures of two deep-water channel systems from the late Miocene of the Transylvanian Basin, Romania offer a fresh insight into the dynamics of erosional and depositional processes. Both channel systems are underlain by mudstone-prone successions; the channel-complex scale incisional surface can only be observed at Tau. Channel-form surfaces interpreted as the base of channel elements and storeys are present in both outcrops. At Tau, the shallow, base-of-slope channel complex consists of amalgamated sandstones separated by thin mudstones. The axis of the deep, slope channel at Daia is characterized by pebble lags, thick amalgamated sandstones that thin towards the margin, and thin mudstones. Backsets, possible cyclic steps, and erosional features, such as rip-up mud-boulders, detachment edges, and ghost bedding also occur. Cycles of incision, bypass with coarse lag accumulation, deposition from gravelly then sandy turbidity currents were repeated numerous times with differing amplitudes, which were followed by the abandonment of the channel complex. Novel incision-infill graphs were created to analyse and compare the cyclicity pattern of deep-water channels. Successive incision depth of channel-form surfaces, and infill height of channel-form bodies aids in distinguishing hierarchical levels, vertical and lateral offsets. Daia and Tau channel complexes show a remarkably similar cyclicity pattern, which might indicate an inherent character of this turbidite system. To investigate whether this pattern is universal, incision-infill graphs of two Laingsburg Karoo channel systems were constructed, based on published data. In all the four examples, a pattern of lateral-then-vertical offset of channel elements was present, and a similarity between channel element-complex and channel storey-element aggradation was found, suggesting a fractal behaviour. Two models are applicable to interpret the revealed pattern of incision-infill graphs, for the Tau and Daia channels: 1) three scales of waxing-waning flow magnitude cyclicity could create the architecture of channel complexes, or 2) the presence of autocyclic channel element incision-infill could eliminate one scale of flow magnitude changes, but two still need to be governed by allocyclic factors. The late Miocene turbidite system in the Transylvanian Basin developed in Lake Pannon, in close relationship with the uplifting Carpathians fringing the basin. As the duration of cycles is shorter than the time range of possible changes in uplift rate or fault activity, tectonically induced cyclicity is discarded. Climatically induced cycles are the most probable controls on varying the flow magnitude that created the complex architecture of channel systems in this lacustrine setting.

The Neogene Transylvanian Basin (TB), enclosed between the eastern and southern Carpathians and the Apuseni Mountains in Romania, is a significant natural gas province with a long production history. In order to improve the (bio) stratigraphic resolution, correlations and dating in the several 100-m-thick upper Miocene (Pannonian) succession of the basin, the largest and most fossiliferous outcrop at Guşteriţa (northeastern part of Sibiu) was investigated and set as a reference section for the Congeria banatica zone in the entire TB. Grey, laminated and massive silty marl, deposited in the deep-water environment of Lake Pannon, was exposed in the ~55-m-high outcrop. The uppermost 25 m of the section was sampled in high resolution (sampling per metres) for macro- and microfossils, including palynology; for authigenic 10Be/9Be dating and for magnetostratigraphy; in addition, macrofossils and samples for authigenic 10Be/9Be isotopic measurements were collected from the lower part of the section as well. The studied sedimentary record belongs to the profundal C. banatica mollusc assemblage zone. The upper 25 m can be correlated to the Hemicytheria tenuistriata and Propontoniella candeo ostracod biozones, the uppermost part of the Spiniferites oblongus, the entire Pontiadinium pecsvaradense and the lowermost part of the Spiniferites hennersdorfensis organic-walled microplankton zones. All samples contained endemic Pannonian calcareous nannofossils, representing the Noelaerhabdus bozinovicae zone. Nine samples were analysed for authigenic 10Be/9Be isotopic measurements. The calculated age data of six samples provided a weighted mean value of 10.42 ± 0.39 Ma. However, three samples within the section exhibited higher isotopic ratios and yielded younger apparent ages. A nearly twofold change in the initial 10Be/9Be ratio is a possible reason for the higher measured isotopic ratios of these samples. Magnetostratigraphic samples showed normal polarity for the entire upper part of the outcrop and can be correlated with the C5n.2n polarity chron (11.056–9.984 Ma, ATNTS2012), which is in agreement with the biostratigraphic data. Based on these newly obtained data and correlation of the biozones with other parts of the Pannonian Basin System, the Guşteriţa section represents the ~ 11.0–10.5 Ma interval, and it is a key section for correlation of mollusc, ostracod, dinoflagellate and calcareous nannoplankton biostratigraphic records within this time interval.

Significance Advances in technology are enabling evaluation for prevention and early detection of age-related chronic diseases associated with premature mortality, such as cancer and cardiovascular diseases. These diseases kill about one-third of men and one-quarter of women between the ages of 50 and 74 years old in the United States. We used whole-genome sequencing, advanced imaging, and other clinical testing to screen 209 active, symptom-free adults. We identified a broad set of complementary age-related chronic disease risks associated with premature mortality., Reducing premature mortality associated with age-related chronic diseases, such as cancer and cardiovascular disease, is an urgent priority. We report early results using genomics in combination with advanced imaging and other clinical testing to proactively screen for age-related chronic disease risk among adults. We enrolled active, symptom-free adults in a study of screening for age-related chronic diseases associated with premature mortality. In addition to personal and family medical history and other clinical testing, we obtained whole-genome sequencing (WGS), noncontrast whole-body MRI, dual-energy X-ray absorptiometry (DXA), global metabolomics, a new blood test for prediabetes (Quantose IR), echocardiography (ECHO), ECG, and cardiac rhythm monitoring to identify age-related chronic disease risks. Precision medicine screening using WGS and advanced imaging along with other testing among active, symptom-free adults identified a broad set of complementary age-related chronic disease risks associated with premature mortality and strengthened WGS variant interpretation. This and other similarly designed screening approaches anchored by WGS and advanced imaging may have the potential to extend healthy life among active adults through improved prevention and early detection of age-related chronic diseases (and their risk factors) associated with premature mortality.

Sequence variation data of the human proteome can be used to analyze 3-dimensional (3D) protein structures to derive functional insights. We used genetic variant data from nearly 150,000 individuals to analyze 3D positional conservation in 4,390 protein structures using 481,708 missense and 264,257 synonymous variants. Sixty percent of protein structures harbor at least one intolerant 3D site as defined by significant depletion of observed over expected missense variation. We established an Angstrom-scale distribution of annotated pathogenic missense variants and showed that they accumulate in proximity to the most intolerant 3D sites. Structural intolerance data correlated with experimental functional read-outsin vitro. The 3D structural intolerance analysis revealed characteristic features of ligand binding pockets, orthosteric and allosteric sites. The identification of novel functional 3D sites based on human genetic data helps to validate, rank or predict drug target binding sitesin vivo.

Polygenic approaches using genome-wide data have been hugely successful in confirming and quantifying the heritability of complex human traits. Here, we highlight their ability to identify potential novel risk variants by looking for variants with pleiotropic effect in genetically overlapping phenotypes.We used LD Score Regression in a sample of 6,315 HIV+ European individuals and 7,247 controls to test for phenotypes genetically overlapping with susceptibility to HIV-1 infection. Using LD Hub, a web tool that performs LD Score Regression, identified two phenotypes with significant genetic overlap: schizophrenia (rG =0.19, p=0.0007 and ulcerative colitis (rG=0.22, p= 0.0061). We further showed that the genetic overlap between HIV acquisition and schizophrenia is likely driven in part by their shared overlap with cannabis use and sexual behavior. BUMHBOX analyses suggested that these genetic overlaps were driven by genome-wide pleiotropy with HIV acquisition rather than heterogeneity within the HIV acquisition sample. The two diseases identified as genetically overlapping with HIV-1 acquisition have >100 associated variants, and we tested if any of them significantly associated with HIV acquisition. We observed three variants that exceeded our threshold for statistical significance. Two of these were eQTLs in whole blood for genes coding for proteins suspected to be involved in HIV biology: rs1819333 in CCR6 (p=0.0002) and rs4932178 in FURIN (p=0.00033). However, no signal was found for these variants in two smaller African samples totaling 1015 cases and 963 controls, though the mode of acquisition and genetic architecture of these populations differed.These results highlight the ability to use polygenic methods to gain new insights into complex diseases and identify potential associations with individual variants. Crucially, the leveraging of existing, publically available data makes these methods a cost-effective approach. In this case, our results add to the evidence for the role of risk taking behavior and inflammation of the bowel in HIV acquisition.Author SummaryThe biology of what puts certain individuals at greater risk of HIV acquisition is poorly understood. Using several novel polygenic methods, we identify supporting evidence for two important factors leading to acquisition. First, the role of an individual’s genetic predisposition to risk taking behaviours such as number of sexual partners, age at first sexual intercourse drug use, and mental health problems. Second, the role of gut inflammation, in particular a genetic overlap between HIV acquisition with inflammatory bowel disease and the potential role of CCR6 during infection.

BACKGROUNDProgress in science and technology have created the capabilities and alternatives to symptom-driven medical care. Reducing premature mortality associated with age-related chronic diseases, such as cancer and cardiovascular disease, is an urgent priority we address using advanced screening detection.METHODSWe enrolled active adults for early detection of risk for age-related chronic disease associated with premature mortality. Whole genome sequencing together with: global metabolomics, 3D/4D imaging using non-contrast whole body magnetic resonance imaging and echocardiography, and 2-week cardiac monitoring were employed to detect age-related chronic diseases and risk for diseases.RESULTSWe detected previously unrecognized age-related chronic diseases requiring prompt (CONCLUSIONSPrecision medicine screening using genomics with other advanced clinical data among active adults identified unsuspected disease risks for age-related chronic diseases associated with premature mortality. This technology-driven phenotype screening approach has the potential to extend healthy life among active adults through improved early detection and prevention of age-related chronic diseases. Our success provides a scalable strategy to move medical practice and discovery toward risk detection and disease modification thus achieving healthier extension of life.SIGNIFICANCE STATEMENTAdvances in science and technology have enabled scientists to analyze the human genome cost-effectively and to combine genome sequencing with noninvasive imaging technologies for alternatives to symptom-driven medical care. Using whole genome sequencing and noninvasive 3D/4D imaging technologies we screened 209 adults to detect age-related chronic diseases, such as cancer and cardiovascular disease. We found unrecognized age-related chronic diseases requiring prompt (

Viral respiratory infections are usually mild and self-limiting; still they exceptionally result in life-threatening infections in previously healthy children. To investigate a potential genetic cause, we recruited 120 previously healthy children requiring support in intensive care because of a severe illness caused by a respiratory virus. Using exome and transcriptome sequencing, we identified and characterized three rare loss-of-function variants in IFIH1, which encodes an RIG-I-like receptor involved in the sensing of viral RNA. Functional testing of the variants IFIH1 alleles demonstrated that the resulting proteins are unable to induce IFN-β, are intrinsically less stable than wild-type IFIH1, and lack ATPase activity. In vitro assays showed that IFIH1 effectively restricts replication of human respiratory syncytial virus and rhinoviruses. We conclude that IFIH1 deficiency causes a primary immunodeficiency manifested in extreme susceptibility to common respiratory RNA viruses.

Understanding the significance of genetic variants in the noncoding genome is emerging as the next challenge in human genomics. We used the power of 11,257 whole-genome sequences and 16,384 heptamers (7-nt motifs) to build a map of sequence constraint for the human species. This build differed substantially from traditional maps of interspecies conservation and identified regulatory elements among the most constrained regions of the genome. Using new Hi-C experimental data, we describe a strong pattern of coordination over 2 Mb where the most constrained regulatory elements associate with the most essential genes. Constrained regions of the noncoding genome are up to 52-fold enriched for known pathogenic variants as compared to unconstrained regions (21-fold when compared to the genome average). This map of sequence constraint across thousands of individuals is an asset to help interpret noncoding elements in the human genome, prioritize variants and reconsider gene units at a larger scale.

Quantitative knowledge of the turnover of different leukocyte populations is a key to our understanding of immune function in health and disease. Much progress has been made thanks to the introduction of stable isotope labeling, the state-of-the-art technique for in vivo quantification of cellular life spans. Yet, even leukocyte life span estimates on the basis of stable isotope labeling can vary up to 10-fold among laboratories. We investigated whether these differences could be the result of variances in the length of the labeling period among studies. To this end, we performed deuterated water-labeling experiments in mice, in which only the length of label administration was varied. The resulting life span estimates were indeed dependent on the length of the labeling period when the data were analyzed using a commonly used single-exponential model. We show that multiexponential models provide the necessary tool to obtain life span estimates that are independent of the length of the labeling period. Use of a multiexponential model enabled us to reduce the gap between human T-cell life span estimates from 2 previously published labeling studies. This provides an important step toward unambiguous understanding of leukocyte turnover in health and disease.

Large scale efforts to sequence whole human genomes provide extensive data on the non-coding portion of the genome. We used variation information from 11,257 human genomes to describe the spectrum of sequence conservation in the population. We established the genome-wide variability for each nucleotide in the context of the surrounding sequence in order to identify departure from expectation at the population level (context-dependent conservation). We characterized the population diversity for functional elements in the genome and identified the coordination of conserved sequences of distal and cis enhancers, chromatin marks, promoters, coding and intronic regions. The most context-dependent conserved regions of the genome are associated with unique functional annotations and a genomic organization that spreads up to one megabase. Importantly, these regions are enriched by over 100-fold of non-coding pathogenic variants. This analysis of human genetic diversity thus provides a detailed view of sequence conservation, functional constraint and genomic organization of the human genome. Specifically, it identifies highly conserved non-coding sequences that are not captured by analysis of interspecies conservation and are greatly enriched in disease variants.

One out of three pediatric sepsis deaths in high income countries occur in previously healthy children. Primary immunodeficiencies have been postulated to underlie fulminant sepsis, but this concept remains to be confirmed in clinical practice. Pseudomonas aeruginosa (P. aeruginosa) is a common bacterium mostly associated with healthcare-related infections in immunocompromised individuals. However, in rare cases, it can cause sepsis in previously healthy children. We used exome sequencing and bioinformatic analysis to systematically search for genetic factors underpinning severe P. aeruginosa infection in the pediatric population. We collected blood samples from 11 previously healthy children, with no family history of immunodeficiency, who presented with severe sepsis due to community-acquired P. aeruginosa bacteremia. Genomic DNA was extracted from blood or tissue samples obtained intravitam or postmortem. We obtained high-coverage exome sequencing data and searched for rare loss-of-function variants. After rigorous filtrations, 12 potentially causal variants were identified. 2 out of 8 (25%) fatal cases were found to carry novel pathogenic variants in primary immunodeficiency genes, including BTK and DNMT3B. This study demonstrates that exome sequencing allows to identify rare, deleterious human genetic variants responsible for fulminant sepsis in apparently healthy children. Diagnosing primary immunodeficiencies in such patients is of high relevance to survivors and affected families. We propose that unusually severe and fatal sepsis cases in previously healthy children should be considered for exome/genome sequencing to search for underlying primary immunodeficiencies.

Background. The impact of human genetic background on low-trauma fracture (LTF) risk has not been evaluated in the context of human immunodeficiency virus (HIV) and clinical LTF risk factors. Methods. In the general population, 6 common single-nucleotide polymorphisms (SNPs) associate with LTF through genome-wide association study. Using genome-wide SNP arrays and imputation, we genotyped these SNPs in HIV-positive, white Swiss HIV Cohort Study participants. We included 103 individuals with a first, physician-validated LTF and 206 controls matched on gender, whose duration of observation and whose antiretroviral therapy start dates were similar using incidence density sampling. Analyses of nongenetic LTF risk factors were based on 158 cases and 788 controls. Results. A genetic risk score built from the 6 LTF-associated SNPs did not associate with LTF risk, in both models including and not including parental hip fracture history. The contribution of clinical LTF risk factors was limited in our dataset. Conclusions. Genetic LTF markers with a modest effect size in the general population do not improve fracture prediction in persons with HIV, in whom clinical LTF risk factors are prevalent in both cases and controls.

Human APOBEC3 cytidine deaminases are intrinsic resistance factors to HIV-1. However, HIV-1 encodes a viral infectivity factor (Vif) that degrades APOBEC3 proteins. In vitro APOBEC3F (A3F) anti-HIV-1 activity is weaker than A3G but is partially resistant to Vif degradation unlike A3G. It is unknown whether A3F protein affects HIV-1 disease in vivo. To assess the effect of A3F gene on host susceptibility to HIV- acquisition and disease progression, we performed a genetic association study in six well-characterized HIV-1 natural cohorts. A common six-Single Nucleotide Polymorphism (SNP) haplotype of A3F tagged by a codon-changing variant (p. I231V, with allele (V) frequency of 48% in European Americans) was associated with significantly lower set-point viral load and slower rate of progression to AIDS (Relative Hazards (RH) = 0.71, 95% CI: 0.56, 0.91) and delayed development of pneumocystis pneumonia (PCP) (RH = 0.53, 95% CI: 0.37–0.76). A validation study in the International Collaboration for the Genomics of HIV (ICGH) showed a consistent association with lower set-point viral load. An in vitro assay revealed that the A3F I231V variant may influence Vif mediated A3F degradation. Our results provide genetic epidemiological evidence that A3F modulates HIV-1/AIDS disease progression., Author Summary Cytidine deaminases of the human APOBEC3 (A3) gene family serve as intrinsic resistance factors to HIV-1 and other retroviruses. HIV-1 encodes the viral infectivity factor (Vif) protein that degrades APOBEC3 proteins via the ubiquitination-proteosomal pathway. APOBEC3F (A3F), unlike APOBEC3G (A3G), is partially resistant to Vif-mediated degradation. The antiviral activity of the A3 family has largely been demonstrated in in vitro experiments, and there is mounting evidence that A3G genetic variants influence HIV disease progression. It is not resolved if A3F protein affects HIV disease in vivo. To assess the in vivo effect of A3F, we performed a genetic association study of genetic variants in A3F for their influence on HIV- acquisition and HIV disease progression. A common A3F haplotype was associated with a 30% reduced rate of AIDS disease progression, lower set-point viral load and delayed development of pneumocystis pneumonia (PCP) in European Americans. This study provides the first epidemiological evidence that A3F might modify HIV-1/AIDS pathogenesis.

Previous genome-wide association studies (GWAS) of HIV-1-infected populations have been underpowered to detect common variants with moderate impact on disease outcome and have not assessed the phenotypic variance explained by genome-wide additive effects. By combining the majority of available genome-wide genotyping data in HIV-infected populations, we tested for association between similar to 8 million variants and viral load (HIV RNA copies per milliliter of plasma) in 6,315 individuals of European ancestry. The strongest signal of association was observed in the HLA class I region that was fully explained by independent effects mapping to five variable amino acid positions in the peptide binding grooves of the HLA-B and HLA-A proteins. We observed a second genome-wide significant association signal in the chemokine (C-C motif) receptor (CCR) gene cluster on chromosome 3. Conditional analysis showed that this signal could not be fully attributed to the known protective CCR5 Delta 32 allele and the risk P1 haplotype, suggesting further causal variants in this region. Heritability analysis demonstrated that common human genetic variation-mostly in the HLA and CCR5 regions-explains 25% of the variability in viral load. This study suggests that analyses in non-European populations and of variant classes not assessed by GWAS should be priorities for the field going forward.

Gerecse Hills, representing the northwesternmost part of the Mesozoic-Paleogene Transdanubian Range, is surrounded by an Upper Miocene-Pliocene (Pannonian) lacustrine to fluvial sedimentary cover to the west and to the north, i.e. towards the Danube – Kisalfold Basin of Slovakia and Hungary. The oldest reports on fossil molluscs from these sediments were published almost 150 years ago. A systematic mapping of the area by geologists of the Geological and Geophysical Institute of Hungary revealed a number of natural and artificial outcrops of fossiliferous Lake Pannon sediments. The present study is based on the molluscs collected from these outcrops, and sedimentological description and interpretation of the embedding sequences.The Upper Miocene deposits near the Gerecse Hills comprise one transgressive-regressive cycle. In the brickyard claypits of Tata, located in the western foreland of the Gerecse Hills, the transgressive limb is represented by the Szak Formation. This formation starts with a thin transgressive lag and consists of homogeneous, bioturbated, bluish-grey clay and argillaceous marl, deposited from suspension in quiet offshore conditions. Characteristic mollusc species include large dreissenids (Congeria czjzeki, C. partschi, C. ungulacaprae), a wide variety of cockles (Lymnocardium tegulatum, L. triangulatocostatum, L. majeri, L. apertum, L. aff. brunnense, L. aff. rogenhoferi, „Pontalmyra” otiophora, Paradacna sp.), and deep-water-adapted pulmonate snails (Valenciennius reussi, Radix kobelti, Gyraulus sp.). This fauna lived in a nutrient-rich and well-oxygenated deep sublittoral environment, at a few tens of meters water depth.Probably the same transgressive event is reflected in the Valyus-kut outcrop (Tardos), in the central part of the hills at 375 m above sea level, where a small patch of Lake Pannon sediments escaped subsequent erosion. In this sequence, lignite-bearing black clay and variegated clays with freshwater and terrestrial molluscs (Theodoxus radmanesti, Melanopsis sturi sturi, M. sturi tortispina, Planorbidae sp., Unionidae sp., Valvata oecsensis, V. obtusaeformis, Oxychilus sp.) are overlain by clay and silt with Congeria czjzeki, Lymnocardium majeri, and other brackish species. This superposition indicates flooding of paludal areas, deepening, and development of intense connection with the sublittoral offshore environment of Lake Pannon.A third – and highly atypical – type of lower contact of Pannonian sediments was discovered in one of the northern valleys of the Gerecse Hills (Ivan-halala Valley, Dunaszentmiklos). A poorly-sorted conglomerate consisting of cobble- and boulder-sized clasts with sandy-clayey matrix overlies directly a Cretaceous sandstone. Imbrication of the clasts indicates N to S transport direction i.e. from the open lake towards the dry land. The matrix contains abundant mollusc fauna, including articulated valves of Congeria aff. simulans turgida, Dreissenomya (Sinucongeria) arcuata, Paradacna sp. and other species. This sediment package is suspected to have been deposited by a tsunami along the rocky coast of Lake Pannon.The regressive limb of the cycle is represented by sediments of the Ujfalu Formation, transported to the area from the uplifted Alps and Western Carpathians probably by the “paleo-Danube” sedimentary system. The Ujfalu Formation either overlies the Szak Formation (further to the west and to the north, in boreholes), or directly overlies the Mesozoic-Paleogene basement along the Danube and in the northern valleys of the Gerecse Hills. This formation consists of few meter thick, shallowing up sedimentary cycles, starting with sublittoral clays (formed below wave base on the prodelta) and ending with littoral sands (deposited on lower shoreface, deltafront or delta plain channels) or even paludal huminitic clays (delta plain marshes or abandoned channel fills). Molluscs reflect this cyclicity; the deepest (shallow sublittoral) fauna is dominated by bivalves, such as Congeria ungulacaprae, Caladacna steindachneri, Paradacna sp., etc. (in the Neszmely brickyard outcrop or in the upper part of Neszmely sand pit). Sublittoral clays may also contain Lymnocardium penslii, Dreissena auricularis, Unio mihanovici and other bivalves, often in reworked position (e.g. Disznos-kut Valley). The littoral sediments are characterized by diverse gastropod fauna (Theodoxus intracarpathicus, Melanopsis caryota, M. pygmaea, M. decollata, M. sturi, M. kupensis, Viviparus sadleri, Valvata sp. and Gyraulus sp.) living in the zone of rooted vegetation. Bivalves also show enhanced diversity in the littoral zone: C. balatonica, C. aff. simulans turgida, Dreissena auricularis, Dreissena sp., Dreissenomya arcuata, Dreissenomya sp., Lymnocardium penslii, L. ponticum, L. vicinum, Euxinicardium schreteri, Paradacna wurmbi and Unio mihanovici are all abundant (e.g. Csekend Valley, Disznos-kut Valley). Huminitic clay layers in the top of the parasequences contain paludal and terrestrial snails (Disznos-kut Valley).The Pannonian sediments and their fossil molluscs in the Gerecse Hills thus reflect gradual flooding of the moderate-relief Mesozoic-Paleogene block of the time, locally either producing a transgressive lag (Tata) or a paludal-lacustrine transitional sequence (Valyus-kut) before the sublittoral clay with Congeria czjzeki (Szak Fm) draped probably much of the recent hills. Sedimentary infilling up to lake level took place in several cycles represented by deltaic parasequences (Ujfalu Fm), each displaying faunal changes from open lacustrine bivalve-dominated to littoral or even paludal snail-dominated assemblages. Sedimentary features indicate syn-sedimentary deformation, which continued subsequently and resulted in significant elevation difference between the transgressive layers in Tata and those in Valyus-kut.Biochronostratigraphic correlations suggest that the age of the entire Pannonian sequence in the Gerecse Hills is between 9.7 and 8.7 Ma (duration of the Lymnocardium ponticum chron). Accordingly, reverse magnetic polarity measured in the lower part of the Tata outcrop, representing the upper part of the Congeria czjzeki zone, suggests correlation with C4Ar, restricting the age of the flooding of the Gerecse hills to the 9.4-9.1 Ma interval. Thus, the age of the entire transgressive-regressive cycle is estimated to have been 9.4-8.7 Ma.

We evaluated the fraction of variation in HIV-1 set point viral load attributable to viral or human genetic factors by using joint host/pathogen genetic data from 541 HIV infected individuals. We show that viral genetic diversity explains 29% of the variation in viral load while host factors explain 8.4%. Using a joint model including both host and viral effects, we estimate a total of 30% heritability, indicating that most of the host effects are reflected in viral sequence variation., Author Summary Viral loads of Human Immunodeficiency Virus infections are correlated between the donor and the recipient of the transmission pair. Similarly, human genetic factors may modulate viral load. In this study we estimate the extents to which viral load is heritable either via the viral genotype (from donor to recipient) or via the host’s Human Leukocyte Antigen (HLA) genotype. We find that a major fraction of inter individual variability is explained by the similarity of the viral genotypes, and that human genetic variation in the HLA region provide little additional explanatory power.

Sequencing projects have identified large numbers of rare stop-gain and frameshift variants in the human genome. As most of these are observed in the heterozygous state, they test a gene?s tolerance to haploinsufficiency and dominant loss of function. We analyzed the distribution of truncating variants across 16,260 protein coding autosomal genes in 11,546 individuals. We observed 39,893 truncating variants affecting 12,062 genes, which significantly differed from an expectation of 12,916 genes under a model of neutral de novo mutation (p

Loss-of-function variants in innate immunity genes are associated with Mendelian disorders in the form of primary immunodeficiencies. Recent resequencing projects report that stop-gains and frameshifts are collectively prevalent in humans and could be responsible for some of the inter-individual variability in innate immune response. Current computational approaches evaluating loss-of-function in genes carrying these variants rely on gene-level characteristics such as evolutionary conservation and functional redundancy across the genome. However, innate immunity genes represent a particular case because they are more likely to be under positive selection and duplicated. To create a ranking of severity that would be applicable to innate immunity genes we evaluated 17,764 stop-gain and 13,915 frameshift variants from the NHLBI Exome Sequencing Project and 1,000 Genomes Project. Sequence-based features such as loss of functional domains, isoform-specific truncation and nonsense-mediated decay were found to correlate with variant allele frequency and validated with gene expression data. We integrated these features in a Bayesian classification scheme and benchmarked its use in predicting pathogenic variants against Online Mendelian Inheritance in Man (OMIM) disease stop-gains and frameshifts. The classification scheme was applied in the assessment of 335 stop-gains and 236 frameshifts affecting 227 interferon-stimulated genes. The sequence-based score ranks variants in innate immunity genes according to their potential to cause disease, and complements existing gene-based pathogenicity scores. Specifically, the sequence-based score improves measurement of functional gene impairment, discriminates across different variants in a given gene and appears particularly useful for analysis of less conserved genes., Author Summary There are well-characterized severe immunodeficiencies associated with loss-of-function variants in innate immunity genes. Genome sequencing projects identify rare stop-gain and frameshift variants in innate immunity genes whose phenotype is uncharacterized. Current methods to estimate the severity of rare stop-gains and frameshifts are based on evolutionary conservation of the gene, the likelihood for redundancy in its function or mutational burden. These parameters are not always applicable to innate immunity genes. We evaluated sequence-level characteristics of more than 30'000 stop-gains and frameshifts and prioritized variants according to their predicted functional consequences. Our scoring approach complements existing tools in the prediction of innate immunity OMIM disease variants and associates with functional readouts such as gene expression. In this framework, we show that many individuals do carry highly pathogenic variants in genes participating in antiviral defense. The clinical assessment of these variants is of significant interest.

Background: There is an ever-increasing volume of data on host genes that are modulated during HIV infection, influence disease susceptibility or carry genetic variants that impact HIV infection. We created GuavaH (Genomic Utility for Association and Viral Analyses in HIV, http://www.GuavaH.org), a public resource that supports multipurpose analysis of genome-wide genetic variation and gene expression profile across multiple phenotypes relevant to HIV biology. Findings: We included original data from 8 genome and transcriptome studies addressing viral and host responses in and ex vivo. These studies cover phenotypes such as HIV acquisition, plasma viral load, disease progression, viral replication cycle, latency and viral-host genome interaction. This represents genome-wide association data from more than 4,000 individuals, exome sequencing data from 392 individuals, in vivo transcriptome microarray data from 127 patients/conditions, and 60 sets of RNA-seq data. Additionally, GuavaH allows visualization of protein variation in similar to 8,000 individuals from the general population. The publicly available GuavaH framework supports queries on (i) unique single nucleotide polymorphism across different HIV related phenotypes, (ii) gene structure and variation, (iii) in vivo gene expression in the setting of human infection (CD4+ T cells), and (iv) in vitro gene expression data in models of permissive infection, latency and reactivation. Conclusions: The complexity of the analysis of host genetic influences on HIV biology and pathogenesis calls for comprehensive motors of research on curated data. The tool developed here allows queries and supports validation of the rapidly growing body of host genomic information pertinent to HIV research.

HIV-1 sequence diversity is affected by selection pressures arising from host genomic factors. Using paired human and viral data from 1071 individuals, we ran >3000 genome-wide scans, testing for associations between host DNA polymorphisms, HIV-1 sequence variation and plasma viral load (VL), while considering human and viral population structure. We observed significant human SNP associations to a total of 48 HIV-1 amino acid variants (p, eLife digest Developing treatments or vaccines for HIV is challenging because the genetic makeup of the virus is constantly changing in an effort to outwit the human immune system. Moreover, the immune system is highly variable as a result of the long-standing co-evolution of humans and microbes. Each individual will try to oppose the invading virus in a unique way, forcing the virus to acquire specific mutations that can be interpreted as the genetic signature of this one-against-one battle. To explore the influence of co-evolution on HIV, Bartha et al. took samples of both human and viral genomes from 1071 individuals infected with HIV, the AIDS virus, and used genotyping and sequencing technology to obtain a comprehensive description of the genetic variation in both. Computational techniques were then used to search for links between variants in the human DNA sequences and variants in the viral sequences. The most common type of genetic variation found in the human genome is a single nucleotide polymorphism, or SNP for short: a SNP is produced when a single nucleotide – an A, C, G or T – is replaced by a different nucleotide. Bartha et al. found that SNPs within the human DNA sequences in their study were linked to variations in 48 amino acids in HIV. Moreover, all these SNPs were found within a group of genes known as the HLA (human leukocyte antigen) system, which encodes for proteins that play a vital role in the immune response. This work identified the areas of the human genome that put pressure on the AIDS virus, and the regions of the virus that serve to escape human control. The approach developed by Bartha et al. allows the interactions between a microbe and a human host to be studied by looking at the genome of the microbe and the genome of the infected person. It also differentiates host-induced mutations that limit the capacity of the virus to do harm from those that are tolerated by the pathogen. A similar strategy could be used to study other infectious diseases. DOI: http://dx.doi.org/10.7554/eLife.01123.002

HIV-1 infects CD4+ T cells and completes its replication cycle in approximately 24 hours. We employed repeated measurements in a standardized cell system and rigorous mathematical modeling to characterize the emergence of the viral replication intermediates and their impact on the cellular transcriptional response with high temporal resolution. We observed 7,991 (73%) of the 10,958 expressed genes to be modulated in concordance with key steps of viral replication. Fifty-two percent of the overall variability in the host transcriptome was explained by linear regression on the viral life cycle. This profound perturbation of cellular physiology was investigated in the light of several regulatory mechanisms, including transcription factors, miRNAs, host-pathogen interaction, and proviral integration. Key features were validated in primary CD4+ T cells, and with viral constructs using alternative entry strategies. We propose a model of early massive cellular shutdown and progressive upregulation of the cellular machinery to complete the viral life cycle., Author Summary Viral pathogens, such as HIV-1, are fully dependent of the cellular machinery to complete the replication cycle. The cell offers a permissive environment, and deploys a number of antiviral defense strategies. The present work follows the process of infection of the cell with simultaneous measurements of viral replication intermediates together with the concurrent assessment of the host transcriptional changes. The main observation is that the cell undergoes a profound modification of its physiology, with a marked early decrease in expression of several thousands of genes, followed by a more discrete increase in the expression of sets of genes that may contribute to the success of the viral replication program. The cell system used in this study has limited response of paradigmatic cellular defense genes. Key features of the experimental model were validated in primary cells and with different viral vectors. The data and model generated here constitute a resource that can be used for the assessment of single gene responses to HIV-1 infection, and as comparative reference for the understanding of other viral and cellular programs, such as those implicated in successful defense against viral infection or in latency.

The 20 residue long Trp-cage is the smallest protein known, and thus has been the subject of several in vitro and in silico folding studies. Here, we report the multistate folding scenario of the miniprotein in atomic detail. We detected and characterized different in- termediate states by temperature de- pendent NMR measurements of the 15 N and 13 C/ 15 N labeled protein, both at neutral and acidic pH values. We de- veloped a deconvolution technique to characterize the invisible—fully folded, unfolded and intermediate—fast ex- changing states. Using nonlinear fitting methods we can obtain both the ther- modynamic parameters (DH F-I , Tm F-I , DCp F-I and DH I-U , Tm I-U , DCp I-U ) and the NMR chemical shifts of the con- formers of the multistate unfolding process. During the unfolding of Trp- cage distinct intermediates evolve: a fast-exchanging intermediate is present under neutral conditions, whereas a slow-exchanging intermediate-pair emerges at acidic pH. The fast-ex- changing intermediate has a native-like structure with a short a-helix in the G 11 -G 15 segment, whereas the slow-ex- changing intermediate-pair presents elevated dynamics, with no detectable native-like residue contacts in which the G 11 � P 12 peptide bond has either cis or trans conformation. Heteronuclear relaxation studies combined with MD simulations revealed the source of backbone mobility and the nature of structural rearrangements during these transitions. The ability to detect struc- tural and dynamic information about folding intermediates in vitro provides an excellent opportunity to gain new insights into the energetic aspects of the energy landscape of protein fold- ing. Our new experimental data offer exceptional testing ground for further computational simulations.

Sequencing projects have identified large numbers of rare stop-gain and frameshift variants in the human genome. As most of these are observed in the heterozygous state, they test a gene’s tolerance to haploinsufficiency and dominant loss of function. We analyzed the distribution of truncating variants across 16,260 autosomal protein coding genes in 11,546 individuals. We observed 39,893 truncating variants affecting 12,062 genes, which significantly differed from an expectation of 12,916 genes under a model of neutral de novo mutation (p, PLoS Computational Biology, 11 (12), ISSN:1553-734X, ISSN:1553-7358

Joint analysis of existing host genetic and HIV sequencing data has been limited so far to HLA alleles and viral mutations. We performed a genome-wide survey of associations between human single nucletide polymorphisms (SNP) and HIV genetic variation across the whole viral genome.

Human immunodeficiency virus (HIV) induces a chronic generalized activation of the immune system, which plays an important role in the pathogenesis of AIDS. This ability of the virus might either be an evolved (adaptive) trait or a coincidental side effect of jumping to a new host species. We argue that selection favours the ability of HIV to induce immune activation at the local sites of infection (e.g. lymph follicles) but not at the systemic level. Immune activation increases the supply of susceptible target cells; however, mutations that increase systemic immune activation benefit all virus variants equally and are therefore selectively neutral. We thus conclude that the generalized immune activation that is probably responsible for pathogenesis is probably not directly under selection.

The article is missing grant details in the Funding section. Please see the correct Funding Statement here: This work was funded by the Swiss National Science Foundation (grant 310030–130699) to AT, AC and NB, by a Grand Challenges Exploration award from the Bill and Melinda Gates Foundation, and by the European Union's Seventh Framework Programme FP7/2007–2013/ under grant agreement n°305762. HFG is supported by SNF grant 127317. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.