Host Genetic Variation Research Articles

The investigation of host genetic variants of toll-like receptor 7 and 8 in COVID-19

Toll-like receptors (TLRs) recognize infectious agents and play an important role in the innate immune system. Studies have suggested that TLR single nucleotide polymorphisms (SNPs) are associated with poor antiviral responses against SARS-CoV-2. Therefore, we aimed to investigate the relationship of TLR7 and TLR8 (SNPs) with COVID-19 disease prognosis. A total of 120 COVID-19 patients, 40 outpatients, 40 clinical ward patients and 40 intensive care unit (ICU) patients were included in the study. TLR7 (rs179009), TLR8-129 C/G (rs3764879) and TLR8 Met1Val (rs3764880) SNPs were genotyped using the PCR-RFLP method. In female patients, individuals carrying AG genotype and G allele for TLR8 Met1Val SNP were found at a higher frequency in patients hospitalized in the ICU than in patients followed in the clinical ward (p < 0.05). In terms of the other two SNPs, no significant difference was found between the groups in females. Furthermore, in male patients, A allele of TLR7 rs179009 SNP was at a higher frequency in patients who have at least one comorbidity than in patients who have no comorbidity (p < 0.05). Our results suggest that TLR8 Met1Val SNP is important in the COVID-19 disease severity in females. Furthermore, TLR7 rs179009 SNP is important in male patients in the presence of comorbid diseases.

Fecal Microbiota Was Reshaped in UCP1 Knock-In Pigs via the Adipose-Liver-Gut Axis and Contributed to Less Fat Deposition.

The relationship between the host gut microbiota and obesity has been well documented in humans and mice; however, few studies reported the association between the gut microbiota and fat deposition in pigs. In a previous study, we generated uncoupling protein 1 (UCP1) knock-in pigs (UCP1 pigs), which exhibited a lower fat deposition phenotype. Whether the gut microbiota was reshaped in these pigs and whether the reshaped gut microbiota contributes to the lower fat content remain unknown. Here, we revealed that the fecal microbiota composition and metabolites were significantly altered under both chow diet (CD) and high-fat/high-cholesterol (HFHC) diet conditions in UCP1 pigs compared to those in wild-type (WT) pigs. The abundance of Oscillospira and Coprococcus and the level of metabolite hyodeoxycholic acid (HDCA) from feces were observed to be significantly increased in UCP1 pigs. An association analysis revealed that Oscillospira and Coprococcus were significantly negatively related to backfat thickness. In addition, after fecal microbiota transplantation (FMT), the mice that were orally gavaged with feces from UCP1 pigs exhibited less fat deposition under both CD and high-fat diet (HFD) conditions, suggesting that the fecal microbes of UCP1 pigs participate in regulating host lipid metabolism. Consistently, HDCA-treated mice also exhibited reduced fat content. Mechanistically, we found that UCP1 expression in white adipose tissue alters the gut microbiota via the adipose-liver-gut axis in pigs. Our study provides new data concerning the cross talk between host genetic variations and the gut microbiota and paves the way for the potential application of microbes or their metabolites in the regulation of fat deposition in pigs. IMPORTANCE This article investigated the effect of the ectopic expression of UCP1 on the regulation of fecal microbiota composition and metabolites and which alters the fat deposition phenotype. Bacteria, including Oscillospira and Coprococcus, and the metabolite HDCA were found to be significantly increased in feces of UCP1 pigs and had a negative relationship with backfat thickness. Mice with fecal microbiota transplantation phenocopied the UCP1 pigs under both CD and HFD conditions, suggesting that the fecal microbes of UCP1 pigs participate in regulating host lipid metabolism. Our study provides new data regarding the cross talk between host genetic variations and the gut microbiota and paves the way for the potential application of microbes or their metabolic production in the regulation of fat deposition in pigs.

Network-based quantitative trait linkage analysis of microbiome composition in inflammatory bowel disease families.

Introduction: Inflammatory bowel disease (IBD) is characterized by a dysbiosis of the gut microbiome that results from the interaction of the constituting taxa with one another, and with the host. At the same time, host genetic variation is associated with both IBD risk and microbiome composition. Methods: In the present study, we defined quantitative traits (QTs) from modules identified in microbial co-occurrence networks to measure the inter-individual consistency of microbial abundance and subjected these QTs to a genome-wide quantitative trait locus (QTL) linkage analysis. Results: Four microbial network modules were consistently identified in two cohorts of healthy individuals, but three of the corresponding QTs differed significantly between IBD patients and unaffected individuals. The QTL linkage analysis was performed in a sub-sample of the Kiel IBD family cohort (IBD-KC), an ongoing study of 256 German families comprising 455 IBD patients and 575 first- and second-degree, non-affected relatives. The analysis revealed five chromosomal regions linked to one of three microbial module QTs, namely on chromosomes 3 (spanning 10.79 cM) and 11 (6.69 cM) for the first module, chr9 (0.13 cM) and chr16 (1.20 cM) for the second module, and chr13 (19.98 cM) for the third module. None of these loci have been implicated in a microbial phenotype before. Discussion: Our study illustrates the benefit of combining network and family-based linkage analysis to identify novel genetic drivers of microbiome composition in a specific disease context.

The Problem of Host and Pathogen Genetic Variability for Developing Strategies of Universally Efficacious Vaccination against and Personalised Immunotherapy of Tuberculosis: Potential Solutions?

Rational vaccination against and immunotherapy of any infectious disease requires knowledge of how protective and non-protective immune responses differ, and how immune responses are regulated, so their nature can be controlled. Strong Th1 responses are likely protective against M tuberculosis. Understanding how immune class regulation is achieved is pertinent to both vaccination and treatment. I argue that variables of infection, other than PAMPs, primarily determine the class of immunity generated. The alternative, non-PAMP framework I favour, allows me to propose strategies to achieve efficacious vaccination, transcending host and pathogen genetic variability, to prevent tuberculosis, and personalised protocols to treat disease.

Antiretroviral Levels in the Cerebrospinal Fluid: The Effect of Inflammation and Genetic Variants.

Neurocognitive impairments are common in people living with HIV. Some conditions, such as chronic inflammation, astrocyte infection and an impaired blood-brain barrier (BBBi), along with host genetic variants in transporter genes, may affect antiretroviral (ARV) exposure in the cerebrospinal fluid (CSF). The aim of this study was to evaluate ARV CSF penetration according to compartmental inflammation, BBB permeability and single-nucleotide polymorphisms (SNPs) in drug transporter encoding genes. CSF neopterin (ELISA), plasma and CSF ARV concentrations (HPLC) and host genetic variants in ABCC2, HNF4α, SLCO1A2 and SLC22A6 (real-time PCR) were measured. Bi- and multivariate analyses were performed for single ARV and classes. We included 259 participants providing 405 paired plasma and CSF samples. CSF/plasma ratios (CPR) showed an increase for NRTIs and nevirapine with low penetrations for the majority of ARVs. At bi-variate analysis, several associations, including the effect of BBBi (emtricitabine, raltegravir), age (zidovudine and darunavir), and high CSF neopterin (NRTIs and border-line for PIs) were suggested. An association was found between genetic variants and integrase strand transfer (ABCC2 and HNF4α), non-nucleoside reverse transcriptase inhibitors (SLCO1A2), and protease inhibitors (SLC22A6). At multivariate analysis age, gender, BMI, and altered BBB were independent predictors of nucleoside reverse transcriptase CSF concentrations; age (for protease inhibitors) and body mass index and altered BBB (integrase strand transfer inhibitors) were also associated with ARV CSF exposure. We describe factors associated with CSF concentrations, showing that demographic, BBB integrity and, partially, genetic factors may be predictors of drug passage in the central nervous system.

Host Genetic Variants Linked to COVID-19 Neurological Complications and Susceptibility in Young Adults-A Preliminary Analysis.

To date, multiple efforts have been made to use genome-wide association studies (GWAS) to untangle the genetic basis for SARS-CoV-2 infection susceptibility and severe COVID-19. However, data on the genetic-related effects of SARS-CoV-2 infection on the presence of accompanying and long-term post-COVID-19 neurological symptoms in younger individuals remain absent. We aimed to examine the possible association between SNPs found in a GWAS of COVID-19 outcomes and three phenotypes: SARS-CoV-2 infection, neurological complications during disease progression, and long-term neurological complications in young adults with a mild-to-moderate disease course. University students (N = 336, age 18-25 years, European ancestry) with or without COVID-19 and neurological symptoms in anamnesis comprised the study sample. Logistic regression was performed with COVID-19-related phenotypes as outcomes, and the top 25 SNPs from GWAS meta-analyses and an MR study linking COVID-19 and cognitive deficits were found. We replicated previously reported associations of the FURIN and SLC6A20 gene variants (OR = 2.36, 95% CI 1.31-4.24) and OR = 1.94, 95% CI 1.08-3.49, respectively) and remaining neurological complications (OR = 2.12, 95% CI 1.10-4.35 for SLC6A20), while NR1H2 (OR = 2.99, 95% CI 1.39-6.69) and TMPRSS2 (OR = 2.03, 95% CI 1.19-3.50) SNPs were associated with neurological symptoms accompanying COVID-19. Our findings indicate that genetic variants related to a severe COVID-19 course in adults may contribute to the occurrence of neurological repercussions in individuals at a young age.

G2GSnake: a Snakemake workflow for host-pathogen genomic association studies.

Joint analyses of paired host and pathogen genome sequences have the potential to enhance our understanding of host-pathogen interactions. A systematic approach to conduct such a joint analysis is through a "genome-to-genome" (G2G) association study, which involves testing for associations between all host and pathogen genetic variants. Significant associations reveal host genetic factors that might drive pathogen variation, highlighting biological mechanisms likely to be involved in host control and pathogen escape. Here, we present a Snakemake workflow that allows researchers to conduct G2G studies in a reproducible and scalable manner. In addition, we have developed an intuitive R Shiny application that generates custom summaries of the results, enabling users to derive relevant insights. G2GSnake is freely available at: https://github.com/zmx21/G2GSnake under the MIT license.

Semantic and Population Analysis of the Genetic Targets Related to COVID-19 and Its Association with Genes and Diseases.

SARS-CoV-2 is a coronavirus responsible for one of the most serious, modern worldwide pandemics, with lasting and multifaceted effects. By late 2021, SARS-CoV-2 has infected more than 180 million people and has killed more than 3 million. The virus gains entrance to human cells through binding to ACE2 via its surface spike protein and causes a complex disease of the respiratory system, termed COVID-19. Vaccination efforts are being made to hinder the viral spread, and therapeutics are currently under development. Toward this goal, scientific attention is shifting toward variants and SNPs that affect factors of the disease such as susceptibility and severity. This genomic grammar, tightly related to the dark part of our genome, can be explored through the use of modern methods such as natural language processing. We present a semantic analysis of SARS-CoV-2-related publications, which yielded a repertoire of SNPs, genes, and disease ontologies. Population data from the 1000 Genomes Project were subsequently integrated into the pipeline. Data mining approaches of this scale have the potential to elucidate the complex interaction between COVID-19 pathogenesis and host genetic variation; the resulting knowledge can facilitate the management of high-risk groups and aid the efforts toward precision medicine.

Association of vitamin D receptor Cdx-2 polymorphism with COVID-19: A case-control study

Background: Host genetic variability has been suggested as an important explanation for inter-individual differences in COVID-19 susceptibility and severity. Most vitamin D actions in the regulation of immunity are mediated by vitamin D receptors (VDRs). Polymorphisms in the VDR gene have been associated with several health outcomes; however, their effects on COVID-19 still need more clarification. This study aims to investigate the association of the VDR SNP (rs11568820, Cdx-2) with susceptibility and inter-individual variability of the severity of COVID-19. Methods: A total of 100 confirmed COVID-19 patients and 100 age and sex-matched controls were enrolled in this study between July and September 2021. COVID-19 patients were further subdivided into severe (n=50) and non-severe (n=50) cases. All participants were subjected to genotyping of Cdx-2 SNP using the allelic discrimination of the Real-time PCR technique and assay of serum 25(OH)D levels by ELISA. Results: The results showed that the homozygous ‘GG’ genotype was significantly higher in patients vs. controls, whereas the heterozygous ‘AG’ genotype was significantly lower in COVID-19 patients. Thus, the heterozygous ‘AG’ genotype is considered the protective genotype. This protection was more significant among males vs. females (P=0.02). However, there were no statistically significant differences in the genotype distributions of VDR Cdx-2 SNP between severe and non-severe patients. Moreover, COVID-19 patients with the ‘AG’ genotype presented higher 25(OH)D levels than the ‘GG’ genotype(P=0.02). Conclusions: VDR SNP (rs11568820, Cdx-2) might be a potential risk factor for COVID-19, particularly among male patients.

Inferring Host Genetic Variation in Key Epidemic Traits: Results from a Parasite Transmission Experiment in Fish

Inferring Host Genetic Variation in Key Epidemic Traits: Results from a Parasite Transmission Experiment in Fish

THE TREND TOWARDS PHENOME-WIDE ASSOCIATION STUDIES (PheWASs) IN COVID-19 RESEARCH

Background: Coronavirus Disease-2019 (COVID-19) appears in individuals asymptomatically and in various symptomatic forms. Symptomatic diversity can result in diagnosis failures, hospitalization, admission to intensive care, multi-organ failure, and death. The causes and risk factors of the severity of disease symptoms are uncertain. This uncertainty can only be resolved by elucidating the effects of host genes and genetic variations on different phenotypes. Aim: This review aimed to emphasize the importance of large-scale genotype-phenotype correlation studies in elucidating the phenotypic diversity in COVID-19 disease. Methods: All publications related to Phenome-Wide Association Study (PheWAS) in the PubMed database were searched. PheWAS studies applied to COVID-19 patients have been identified. In addition, studies applied to the genome-wide association study (GWAS)- Electronic health records (EHRs) data and additionally matched to the gene expression data were systematically reviewed. The latest PheWAS methodology and its importance in Large-scale genotype-phenotype correlations are discussed within the context of published COVID-19 studies. Results: According to our PubMed search data, there are few PheWAS studies on COVID-19 disease. This review explains the use of PheWAS studies applied to health records and GWAS data, and colocalization studies applied to expression quantitative trait locus (eQTL) analysis to understand the phenotypic variability of COVID-19. Discussion; Although there is a very limited number of PheWAS studies on COVID-19 diseases, these studies have obtained important data. At the current stage, there is a need for such studies in COVID-19 research. Conclusions: PheWAS is an ideal method for large-scale genotype-phenotype correlation studies that can reveal genetic diversity and phenotypic diversity in the pathophysiology of the disease.

The Use of Host Biomarkers for the Management of Invasive Fungal Disease.

Invasive fungal disease (IFD) causes severe morbidity and mortality, and the number of IFD cases is increasing. Exposure to opportunistic fungal pathogens is inevitable, but not all patients with underlying diseases increasing susceptibility to IFD, develop it. IFD diagnosis currently uses fungal biomarkers and clinical risk/presentation to stratify high-risk patients and classifies them into possible, probable, and proven IFD. However, the fungal species responsible for IFD are highly diverse and present numerous diagnostic challenges, which culminates in the empirical anti-fungal treatment of patients at risk of IFD. Recent studies have focussed on host-derived biomarkers that may mediate IFD risk and can be used to predict, and even identify IFD. The identification of novel host genetic variants, host gene expression changes, and host protein expression (cytokines and chemokines) associated with increased risk of IFD has enhanced our understanding of why only some patients at risk of IFD actually develop disease. Furthermore, these host biomarkers when incorporated into predictive models alongside conventional diagnostic techniques enhance predictive and diagnostic results. Once validated in larger studies, host biomarkers associated with IFD may optimize the clinical management of populations at risk of IFD. This review will summarise the latest developments in the identification of host biomarkers for IFD, their use in predictive modelling and their potential application/usefulness for informing clinical decisions.

Genetic variation in P-element dysgenic sterility is associated with double-strand break repair and alternative splicing of TE transcripts.

The germline mobilization of transposable elements (TEs) by small RNA mediated silencing pathways is conserved across eukaryotes and critical for ensuring the integrity of gamete genomes. However, genomes are recurrently invaded by novel TEs through horizontal transfer. These invading TEs are not targeted by host small RNAs, and their unregulated activity can cause DNA damage in germline cells and ultimately lead to sterility. Here we use hybrid dysgenesis-a sterility syndrome of Drosophila caused by transposition of invading P-element DNA transposons-to uncover host genetic variants that modulate dysgenic sterility. Using a panel of highly recombinant inbred lines of Drosophila melanogaster, we identified two linked quantitative trait loci (QTL) that determine the severity of dysgenic sterility in young and old females, respectively. We show that ovaries of fertile genotypes exhibit increased expression of splicing factors that suppress the production of transposase encoding transcripts, which likely reduces the transposition rate and associated DNA damage. We also show that fertile alleles are associated with decreased sensitivity to double-stranded breaks and enhanced DNA repair, explaining their ability to withstand high germline transposition rates. Together, our work reveals a diversity of mechanisms whereby host genotype modulates the cost of an invading TE, and points to genetic variants that were likely beneficial during the P-element invasion.

Detection of IL-17A and IL-17F gene polymorphism in recurrent and disseminated pityriasis versicolor: a case-control study

Recurrent and disseminated pityriasis versicolor (RDPV) is a common clinical entity, characterized by its recurrent and disfiguring nature. Studies demonstrated host genetic variations in the immune response, especially the role of IL-17 in antifungal immunity. This study aimed to detect whether IL-17A and F gene polymorphisms are found in cases of RDPV. It included 100 cases of RDPV and 100 age and sex matched controls, from which EDTA blood samples were taken for single-nucleotide polymorphism analysis. IL-17A (rs2275913) and F (rs763780) were associated with a significantly increased incidence of developing RDPV. IL-17A and F gene polymorphism could be implicated as a risk factor for the development of RDPV.

Associations between host genetic variants and Herpes Simplex Labialis in the TwinsUK cohort

ObjectivePrevious literature supports controversial results about the role of host genetic factors in the reactivation of Herpes Simplex Labialis (HSL). The objective of this study is to explore the association between different putative single nucleotide polymorphisms (SNPs) and self-reported HSL reactivation in the TwinsUK cohort. Design1761 participant were recruited for this study from the TwinsUK register. Blood collection and HSL questionnaire were completed for a subset of 595 participants (age 61.9, dizygotic twins 62.8%). Blood was stored at −80 °C and DNA analysed from all samples. The potential associations between candidate SNPs and HSL were assessed using a set of 40 SNPs, including SNPs previously correlated with HSL disease and other SNPs previously associated with the oral microbiota. Results235 participants reported to have experienced ‘cold sores’ at least once in their lives, and 160 reported reinfection episodes. No association was detected between rs243588, rs1047978, rs1062202 genotypes and both occurrence of cold sores (p = 0.172, p = 0.360, p = 0.742) and their recurrence (p = 0.160, p = 0.105,p = 0.746). Among other investigated SNPs, a nominal significant association was detected between Vitamin D Receptor (VDR) Fok I (rs2228570) and both history of HSL (p = .001) and its recurrence (p = .007). ConclusionsA single nucleotide polymorphism in the VDR gene may be correlated with cold sores and their recurrence.

Why vaccines fail against Piscirickettsiosis in farmed salmon and trout and how to avoid it: A review.

Piscirickettsiosis is the most severe, persistent, and damaging disease that has affected the Chilean salmon industry since its origins in the 1980s. As a preventive strategy for this disease, different vaccines have been developed and used over the last 30 years. However, vaccinated salmon and trout frequently die in the sea cages and the use of antibiotics is still high demonstrating the low efficiency of the available vaccines. The reasons why the vaccines fail so often are still debated, but it could involve different extrinsic and intrinsic factors. Among the extrinsic factors, mainly associated with chronic stress, we can distinguish: 1) biotic including coinfection with sea lice, sealions attacks or harmful algal blooms; 2) abiotic including low oxygen or high temperature; and 3) farm-management factors including overcrowding or chemical delousing treatments. Among the intrinsic factors, we can distinguish: 1) fish-related factors including host's genetic variability (species, population and individual), sex or age; 2) pathogen-related factors including their variability and ability to evade host immune responses; and 3) vaccine-related factors including low immunogenicity and poor matches with the circulating pathogen strain. Based on the available evidence, in order to improve the development and the efficacy of vaccines against P. salmonis we recommend: a) Do not perform efficacy evaluations by intraperitoneal injection of pathogens because they generate an artificial protective immune response, instead cohabitation or immersion challenges must be used; b) Evaluate the diversity of pathogen strains in the field and ensure a good antigenic match with the vaccines; c)Investigate whether host genetic diversity could be improved, e.g. through selection, in favor of better and longer responses to vaccination; d) To reduce the stressful effects at the cage level, controlling the co-infection of pathogens and avoiding fish overcrowding. To date, we do not know the immunological mechanisms by which the vaccines against P. salmonis may or may not generate protection. More studies are required to identify what type of response, cellular or molecular, is required to develop effective vaccines.

Host genetic variability and determinants of severe COVID-19

Since the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak, convergent studies have provided evidence that host genetic background may contribute to the development of severe coronavirus disease (COVID-19). Here, we summarize how some genetic variations, such as in SARS-CoV-2 receptor angiotensin-converting enzyme 2 or interferon signaling pathway, may help to understand why some individuals can develop severe COVID-19.

Distinct effects of three Wolbachia strains on fitness and immune traits in Homona magnanima.

The endosymbiotic bacterium Wolbachia occasionally increases host fitness or manipulates host reproductions to enhance vertical transmission. Multiple Wolbachia strains can coinfect the same host individual, which alters the density as well as phenotypes of the bacteria. However, the effects of Wolbachia coinfection on host fitness remain largely unknown. Here, we examined the effects of three phylogenetically distinct Wolbachia strains, wHm-a, wHm-b, and wHm-c, on host fitness by comparing non-infected, singly infected, and triply infected Homona magnanima lines within a fixed genetic background. By examining the effects of Wolbachia on host longevity, survivorship, and reproduction, we demonstrated that single infection with either wHm-b or wHm-c reduced host reproduction, but the triple infection led to the highest intrinsic growth rate. Susceptibility to the natural pathogens such as viruses and fungi was not different among the lines regardless of Wolbachia infection status. Cellular and humoral immunities were not affected by Wolbachia in females, whereas phenoloxidase activity was suppressed in males of all Wolbachia-infected lines, implying that it was a result of the mother's curse hypothesis or a strategy of Wolbachia to increase their horizontal transmission efficiency. Although how the host's genetic diversity affects the Wolbachia fitness effects is yet unknown, our findings indicated that the effects of Wolbachia are deeply influenced by infection status and that Wolbachia could change symbiotic strategy depending on host sex and transmission route.

Host specificity and genetic diversity of Bartonella in rodents and shrews from Eastern China.

Bartonella are vector-borne gram-negative facultative intracellular bacteria causing emerging infectious diseases worldwide, and two thirds of known Bartonella species are carried by rodents. We captured rodents, shrewsand rodent ectoparasitic mites in rural areas of Qingdao City, Shandong Province, China from 2012 to 2021 and used the animal spleen tissues for the PCR amplification of Bartonella gltA and rpoB genes. PCR showed 9.4% (40/425) rodents, and 5.1% (12/235) shrews were positive for Bartonella. Seven Bartonella species including three novel species were identified in five rodent species and one shrew species, indicating the abundance and genetic diversity of Bartonella in rodents and shrews. The infection rate of each Bartonella species in the animal species was as below: novel Candidatus Bartonella crocidura in shrews Crocidura lasiura (5.1%, 12/235); novel Candidatus Bartonella cricetuli in hamsters Tscherskia triton (20%, 9/45); novel Candidatus Bartonella muris in striped field mice Apodemus agrarius (4.2%, 7/168) and house mice Mus musculus (1.5%, 2/135); Bartonella fuyuanensis in striped field mice (8.9%, 15/168) and house mice (0.7%, 1/135); Bartonella rattimassiliensis and Bartonella tribocorum in brown rats Rattus norvegicus (6.7%, 3/45 and 4.2%, 2/45, respectively); Bartonella queenslandensis in Chinese white-bellied rat Niviventer confucianus (12.5%, 1/8). These results suggest that Bartonella infected a variety of rodent and shrew species with high infection rate, but each Bartonella specie is restricted to infect only one or a few genetically closely related rodent species. In addition, Candidatus Bartonella cricetuli, Candidatus Bartonella muris and Bartonella coopersplainsensis were found in chigger Walchia micropelta (33.3%, 3/9), and B. fuyuanensis were found in chigger Leptotrombidium intermedium (4.1%, 1/24), indicating chiggers may be reservoirs of Bartonella. In conclusion, abundant genetic diversified Bartonella species are found to infect rodents, shrews and chiggers, but each Bartonella species has a strict rodent animal host specificity; and chigger mites may play a role in Bartonella transmission.

Heterogeneity of immune control in chronic hepatitis B virus infection: Clinical implications on immunity with interferon-α treatment and retreatment.

Hepatitis B virus (HBV) infection is a global public health issue. Interferon-α (IFN-α) treatment has been used to treat hepatitis B for over 20 years, but fewer than 5% of Asians receiving IFN-α treatment achieve functional cure. Thus, IFN-α retreatment has been introduced to enhance antiviral function. In recent years, immune-related studies have found that the complex interactions between immune cells and cytokines could modulate immune response networks, in-cluding both innate and adaptive immunity, triggering immune responses that control HBV replication. However, heterogeneity of the immune system to control HBV infection, particularly HBV-specific CD8+ T cell heterogeneity, has consequ-ential effects on T cell-based immunotherapy for treating HBV infection. Altogether, the host's genetic variants, negative-feedback regulators and HBV components affecting the immune system's ability to control HBV. In this study, we reviewed the literature on potential immune mechanisms affecting the immune control of HBV and the clinical effects of IFN-α treatment and retreatment.