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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. We investigated whether ERAP variants influence HLA-associated HIV-1 adaptation with demonstrable effects on overall HIV-1 disease outcome. Utilizing host and viral data of 249 West Australian individuals with HIV-1 subtype B infection, we identified a novel association between two linked ERAP2 single nucleotide polymorphisms (SNPs; rs2248374 and rs2549782) with plasma HIV RNA concentration (viral load) (P adjusted = 0.0024 for both SNPs). Greater HLA-associated HIV-1 adaptation in the HIV-1 Gag gene correlated significantly with higher viral load, lower CD4+ T cell count and proportion; P = 0.0103, P = 0.0061, P = 0.0061, respectively). When considered together, there was a significant interaction between the two ERAP2 SNPs and HLA-associated HIV-1 adaptation on viral load (P = 0.0111). In a comprehensive multivariate model, addition of ERAP2 haplotypes and HLA associated adaptation as an interaction term to known HLA and CCR5 determinants and demographic factors, increased the explanatory variance of population viral load from 17.67% to 45.1% in this dataset. These effects were not replicated in publicly available datasets with comparably sized cohorts, suggesting that any true global epistasis may be dependent on specific HLA-ERAP allelic combinations. Our data raises the possibility that ERAP2 variants may shape peptide repertoires presented to HLA class I-restricted T cells to modulate the degree of viral adaptation within individuals, in turn contributing to disease variability at the population level. Analyses of other populations and experimental studies, ideally with locally derived ERAP genotyping and HLA-specific viral adaptations are needed to elucidate this further. Author summary: HIV infection outcome is variable between individuals and understanding the factors that impact this variation is important for efforts towards a HIV cure or vaccine. Here, we found that the level of HIV in the blood is affected by whether an individual carries a specific form of ERAP2, a molecule that influences processing and presentation of the virus to the immune system, as well as the degree to which HIV has mutated to adapt to immune responses. We also show that the interaction of ERAP2 and other known genetic factors explains greater variation in infection outcome than these factors alone. These findings expand our knowledge of the potential importance of viral processing and presentation in the immune response to HIV. [ABSTRACT FROM AUTHOR]

Standard single-cell RNA-sequencing alignment pipelines often misassign killer immunoglobulin-like receptor (KIR) transcripts, leading to inaccuracies in quantifying KIR expression. This study found that activating KIR transcripts are frequently misclassified as inhibitory KIR expression, resulting in a skewed representation of the KIR repertoire. The misassignment is attributed to limitations in the analysis pipelines and the reference genomes used for alignment. The study suggests that realigning the data to a modified reference genome can improve the detection of KIR diversity, but challenges still exist due to the high homology among KIR genes. The findings highlight the need for caution when interpreting KIR expression in single-cell RNA-sequencing data and emphasize the importance of considering potential biases in reference genomes. [Extracted from the article]

Anorexia nervosa (AN) is a polygenic, severe metabopsychiatric disorder with poorly understood aetiology. Eight genome wide significant loci have been identified and single nucleotide polymorphisms (SNPs) account for ∼11-17% heritability (Watson et al., 2019). A key challenge to understanding mechanisms through which these loci alter AN risk is the uncertainty around which variants in the risk region drive the effect, as linkage disequilibrium (LD) across these regions means variants other than the most strongly associated SNP may be relevant. Therefore, it is important to define the spectrum of genetic variants in these regions. Advancements in long read genetic sequencing technologies such as nanopore sequencing, present a heretofore unseen opportunity to interrogate complex genetics at base pair resolution in individuals with high accuracy. We implemented a novel pilot approach with targeted nanopore sequencing (Oxford Nanopore Technologies) of the eight loci associated with AN in 10 individuals with AN. Sequencing data was aligned to human reference genome GRCh38. We leveraged a variety of publicly available variant calling algorithms and databases, including calculating LD for SNPS identified in the recent AN genome wide association study (GWAS) with the newly developed TopLD tool, and variation annotations by Variant Effect Predictor (VEP), to characterise these loci. The primary focus was on less characterised variant types, including retrotransposons, tandem repeats, and short tandem repeats in regions of high LD with functional variant annotations. Target regions were clearly enriched (average coverage per sample ≥10.3X) and contained putatively relevant variants. Prioritised variants primarily occurred in introns, intergenic regions, or, in the case of one variant overlapping FOXP1, in the 3ʹ UTR. Notably, we identified a SINE-VNTR-Alu like sub-family D element (SVA-D), ∼2000bp, in the lead GWAS target region, intergenic with IP6K2 and PRKAR2A. This element had reported variations (both expansions and contractions) in all samples and bordered a precipitous decrease in LD. This variant overlaps several putative regulatory elements and interaction regions for surrounding genes. We successfully applied adaptive sampling to uncover genetic variation at base pair resolution in eight selected AN associated loci. Our results highlight the potential of this technology for uncovering novel or complex variation not captured by GWAS potentially underpinning risk regions. We present a subset of prioritized variants as examples of targets for investigation. While preliminary, variants such as the polymorphic SVA-D element in the lead GWAS locus could contribute to mechanisms of phenotypic risk. Based on protein, gene, and regulatory annotations in the UCSC Genome Browser, we speculate this SVA variant may influence regulation of several neighbouring genes, including already implicated plausible players in AN biology. This study is an exploratory investigation, not powered to detect significant effects, results interpreted cautiously; however, the rich variation with putative regulatory effects captured in this pilot study, much of which has not been previously explored, provides new opportunities for improved understanding of genetic risk mechanisms AN. We aim to continue characterisation of these types of genetic elements in larger, more diverse cohorts, to better understand whether and how these variants may contribute to risk. [ABSTRACT FROM AUTHOR]

Host immunity can exert a complex array of selective pressures on a pathogen, which can drive highly mutable RNA viruses towards viral escape. The plasticity of a virus depends on its rate of mutation, as well as the balance of fitness cost and benefit of mutations, including viral adaptations to the host's immune response. Since its emergence, SARS-CoV-2 has diversified into genetically distinct variants, which are characterised often by clusters of mutations that bolster its capacity to escape human innate and adaptive immunity. Such viral escape is well documented in the context of other pandemic RNA viruses such as the human immunodeficiency virus (HIV) and influenza virus. This review describes the selection pressures the host's antiviral immunity exerts on SARS-CoV-2 and other RNA viruses, resulting in divergence of viral strains into more adapted forms. As RNA viruses obscure themselves from host immunity, they uncover weak points in their own armoury that can inform more comprehensive, long-lasting, and potentially cross-protective vaccine coverage. [ABSTRACT FROM AUTHOR]

T cell exhaustion is a hallmark of hepatitis C virus (HCV) infection and limits protective immunity in chronic viral infections and cancer. Limited knowledge exists of the initial viral and immune dynamics that characterise exhaustion in humans. We studied longitudinal blood samples from a unique cohort of individuals with primary infection using single-cell multi-omics to identify the functions and phenotypes of HCV-specific CD8+ T cells. Early elevated IFN-γ response against the transmitted virus is associated with the rate of immune escape, larger clonal expansion, and early onset of exhaustion. Irrespective of disease outcome, we find heterogeneous subsets of progenitors of exhaustion, based on the level of PD-1 expression and loss of AP-1 transcription factors. Intra-clonal analysis shows distinct trajectories with multiple fates and evolutionary plasticity of precursor cells. These findings challenge the current paradigm on the contribution of CD8+ T cells to HCV disease outcome and provide data for future studies on T cell differentiation in human infections. The early immune response following exposure to HCV is not fully explored. Here the authors use single cell analysis and immune profiling to relate the infection sequence and immune response to early HCV infection showing that exhausted phenotypes of T cells arise early post infection. [ABSTRACT FROM AUTHOR]