Hepatitis C virus (HCV) infection remains a global health concern. This study analyzed 95,864 plasma samples from Saudi patients between 2011 and 2022 to examine HCV seroconversion, viral load, and genotype distribution. Serological screening was performed using the ARCHITECT anti-HCV assay, and HCV RNA levels were quantified with real-time RT-PCR. Of the 970 HCV-positive cases, 47.9 % experienced spontaneous recovery, while 52.1 % had persistent infection. The annual seropositivity rate declined significantly from 2.05 % in 2011 to 0.34 % in 2022. Genotyping of 107 persistently infected samples showed genotypes 4 (49.5 %) and 1a (17.8 %) as the most common, with other genotypes appearing less frequently. Additionally, 13 (12.1 %) samples had untypable genotypes. This study highlights the decrease in HCV infection rates, the high rate of spontaneous recovery, and the predominance of genotypes 4 and 1a. Ongoing surveillance and genotyping, including untypable cases, are essential for effective HCV management in Saudi Arabia.

WHO recommends treating hepatitis C infection with one of three antiviral combinations for 8-12 weeks. No randomised trials have compared these regimens, and high cure rates might be achievable with shorter durations of therapy. We aimed to compare sofosbuvir-daclatasvir with sofosbuvir-velpatasvir, and to evaluate potential novel treatment strategies.

We conducted a multi-arm, open-label, randomised controlled non-inferiority trial in two public hospitals in Viet Nam. Adults (aged ≥18 years) with chronic hepatitis C infection and mild-to-moderate liver fibrosis were eligible. Recruitment was stratified by centre and viral genotype (1-5 vs 6) with 1:1 random allocation to an oral fixed-dose combination of sofosbuvir 400 mg plus daclatasvir 60 mg (sofosbuvir-daclatasvir) or sofosbuvir 400 mg plus velpatasvir 100 mg (sofosbuvir-velpatasvir). Participants were simultaneously factorially randomly assigned to one of four treatment strategies: 12 weeks' standard of care (SOC); 4 weeks' therapy with four weekly PEGylated interferon alfa-2a subcutaneous injections; induction and maintenance therapy with 2 weeks' standard therapy followed by 10 weeks' therapy 5 days a week; and response-guided therapy (RGT) for 4, 8, or 12 weeks determined by viral load on day 7. The primary outcome was sustained virological response (SVR) 12 weeks after treatment completion, analysed in all evaluable participants regardless of actual treatment received. We chose a 5% non-inferiority margin for the drug comparison, and a 10% non-inferiority margin for the treatment strategy comparisons. Safety was assessed in all randomised participants. This trial is registered with ISRCTN, 61522291, and is completed.

Between June 19, 2020, and May 10, 2023, 624 participants were randomised (470 [75%] were male and 154 [25%] were female). 296 (47%) had genotype 6 and 328 (53%) had genotypes 1-5. The primary outcome was assessable in 609 (98%) participants. SVR occurred in 294 (97%) of 302 participants in the sofosbuvir-daclatasvir group and 292 (95%) of 307 participants in the sofosbuvir-velpatasvir group (risk difference 2·2%, 90% credible interval [CrI] -0·2 to 4·8, within the 5% non-inferiority margin; 93% probability that sofosbuvir-daclatasvir is superior to sofosbuvir-velpatasvir). SVR occurred in 148 (99%) of 150 in the SOC group, 143 (94%) of 152 in the 4-week antiviral plus interferon group (-4·5%, 90% CrI -8·3 to -1·3), 151 (99%) of 152 in the induction-maintenance group (0·6%, -1·1 to 2·7), and 144 (93%) of 155 in the RGT group (-5·7%, -9·6 to -2·3); all risk differences were within the 10% non-inferiority margin. Serious adverse events were rare (11 [4%] of 313 participants in the sofosbuvir-velpatasvir group vs six [2%] of 311 in the sofosbuvir-daclatasvir group; risk difference -1·6% [95% CrI -4·2 to 0·8]) with no evidence of differences between regimens or strategies, but adverse reactions were very common in the 4-week antiviral plus interferon group compared with the other treatment strategies (risk difference vs SOC group, 66·8% [59·2 to 74·0]; p<0·0001).

Sofosbuvir-daclatasvir was non-inferior to sofosbuvir-velpatasvir. High efficacy was seen with novel strategies, which might help to inform approaches to treatment for harder-to-reach populations.

Wellcome Trust.

Host factors, such as innate immune response, genetic polymorphisms, age, and body weight are important determinants of susceptibility, severity, and responsiveness to treatment of influenza disease. However, the molecular mechanisms underlying these clinical associations remain poorly characterized, particularly regarding IFN-λ-mediated antiviral responses.

Wild-type mice and IL-28B-/- mice were used to systematically investigate the antiviral and anti-inflammatory functions of IL-29 or IL-28, respectively. Plaque assay and DNA genotyping were conducted to determine the correlations between IFN-λ polymorphisms and H1N1 infection outcomes. ELISA, Real-time PCR and luciferase reporter assays were carried out to explore the mechanism.

IFN-λ plays an important antiviral and immunoprotective role in H1N1 infection. Specifically, IL-29 and IL-28 exhibit important dual antiviral and anti-inflammaroty roles. Age factor also affects H1N1 clearance and therapeutic responsiveness. Human alveolar epithelial cells (AECs) from young donors support higher H1N1 replication and weak response to antiviral treatment with IL-29. Rs12979860 (IL-28 C/T), rs8099917 (IL-28 T/G) and rs30461 (IL-29 A/G), the three identified single nucleotide polymorphisms (SNPs) in IFNL genes, are also associated with H1N1 outcomes. AECs from rs12979860TT and rs8099917GG donors exhibit higher H1N1 replication and nonresponsiveness to IL-29 antiviral therapy. AECs from rs12979860 TT donors also produce lower levels of IFN and exhibit inhibited promoter activity of IL-29 in response to H1N1 infection. In addition, increased allele frequencies of rs12979860 T and rs8099917 G were associated with higher BMI, another important factor influencing H1N1 susceptibility.

This is the first study to comprehensively explore the impact of host factors, especially IFN-λ polymorphisms, on H1N1 virus infection. Further elucidation of the underlying mechanisms may help to develop novel prevention and treatment strategies for influenza virus infection.

The single nucleotide polymorphism rs12979860 is associated with the production of IFNλ4, a type III interferon, which offers protection from viral infection via its proinflammatory properties. We investigated if a genetically determined increase in IFNλ4 affects disease progression in SARS-CoV-2. This prospective, single-center study involved critically ill SARS-CoV-2 patients admitted to the intensive care unit. We performed genotyping for rs12979860 and analyzed daily laboratory data. Genotype frequencies were compared with an external validation cohort. Critically ill individuals with COVID-19 (n = 184; 29.3% women) were included. Median age was 63 years. The TT genotype was present in 11%, CT in 48% and CC in 41%. At baseline, CRP, ferritin, transferrin and neopterin did not differ significantly between groups. Longitudinal analysis revealed significant genotype-dependent differences in CRP, ferritin and neopterin with the highest peak in TT patients after 10-15 days. A higher need for renal replacement therapy (31.6% vs. 11.7%, p = 0.044) and mechanical ventilation (22 days vs. 15 days, p = 0.018) was observed in the TT group. The SNP rs12979860 near IFNL4 is associated with distinct inflammatory trajectories in critically ill COVID-19 patients. Genetic determinants of the immune response influence the severity of inflammation and clinical outcomes in severe COVID-19.

Hepatitis C virus (HCV) infection affects approximately 3.9 million people in the United States (U.S.), leading to 8000 to 10,000 deaths annually. Despite advancements in curative treatments since 2014, effective strategies targeting high-risk groups are crucial. This study examines HCV-related mortality trends from 1999 to 2020, focusing on demographic and regional disparities using the CDC WONDER database. A retrospective analysis was conducted using the CDC WONDER database. HCV-related deaths were identified using the International Classification of Diseases, Tenth Revision (ICD-10) codes B17.1 and B18.2. Mortality data were categorised by gender, age, race/ethnicity, region, place of death and urbanisation status. We calculated crude mortality rates (CRs) and age-adjusted mortality rates (AAMRs) per 100,000 population. Joinpoint regression analysis identified significant changes in mortality trends. A total of 324,008 HCV-related deaths were reported. The overall AAMR was 4.27 (95% Confidence Interval [CI]: 4.25 to 4.28). Mortality increased from 1999 to 2014 (1999 to 2007 Annual Percent Change [APC]: 5.00; 2007 to 2014 APC: 1.95) and declined sharply from 2014 to 2020 (APC: -7.11). Males exhibited higher mortality (AAMR: 6.28) than females (AAMR: 2.42). The 55-64 years age group had the highest CR (16.38), while non-Hispanic (NH) American Indians had the highest rate (AAMR: 8.72) among racial groups. Regionally, the South had the highest AAMR (5.80), nearly double that of the West (2.23) and Midwest (2.62). HCV-related mortality trends show significant demographic disparities and regional variations. Targeted interventions are essential to reduce HCV burden, particularly among vulnerable groups.

Analyze the infection status of four blood-borne infectious diseases, namely hepatitis B, hepatitis C, syphilis, and acquired immune deficiency syndrome (AIDS), among pregnant women from different ethnic groups in Yili, Xinjiang. The objective is to assess the prevalence of four infectious diseases among pregnant women in this region and provide reference for the prevention and elimination of mother-to-child transmission. Pregnant women of Han and Uygur ethnicity who underwent prenatal screening at our outpatient clinic between 2016 and 2022 were selected for screening for hepatitis B virus surface antigen (HBsAg), antibody to hepatitis C virus (anti-HCV), antibody to treponema pallidum (anti-TP) and antibody to human immunodeficiency virus (anti-HIV) using an enzyme-linked immunosorbent assay (ELISA). A total of 13,437 pregnant women were tested, aged between 18 and 47. The positive rate of four infectious disease markers in Han and Uygur pregnant women in this region was 6.97 % (936/13,437). The total positive rate of HBsAg was 6.44 % (865/13,437), among which the Han women of HBsAg positive rate was 6.63 % (836/12,608), and the HBsAg positive rate in Uygur women was 3.63 % (29/829) (χ2=12.673, P = 0.000); the total positive rate of anti-HCV was 0.16 % (21/13,437), of which the anti-HCV positive rate of Han women was 0.15 % (19/12,608), and anti-HCV positive rate in Uygur women was 0.24 % (2/829). (χ2=0.034, P = 0.853); the total positive rate of anti-TP was 0.34 % (46/13,437), of which the positive rate of anti-TP in Han women was 0.24 % (30/12,608), and the positive rate of anti-TP in Uygur women was 1.93 % (16/829) (χ2=65.280, P = 0.000); the total positive rate of anti-HIV was 0.03 % (4/13,437), of which Han nationality anti-HIV positive rate was 0 % (0/12,608), and the anti-HIV positive rate in Uygur nationality was 0.48 % (4/829) (P = 0.000). The positive rate of hepatitis B surface antibodies (anti-HBs) positive in Han nationality was 56.44 % (7116/12,608) and the positive rate of anti-HBs in Uygur nationality was 41.62 % (345/829) (χ2=65.219, P = 0.000); the all-negative detection rate of Han nationality was 29.04 % (3661/12,608) and the Uygur nationality of all-negative detection rate was 46.20 % (383/829) (χ2=104.352, P = 0.000). Our results suggest that the difference in infection rates between Han and Uygur pregnant women in Yili, Xinjiang, may be related to the different genetic susceptibility among different ethnic groups.

Monocyte chemoattractant protein-1 (MCP-1) is regarded as a crucial proinflammatory cytokine that controls the migration and entry of macrophages. It has been demonstrated that chemokine ligand 2 and its receptor, chemokine receptor 2, are both implicated in several liver disorders. In a similar context, immunity mediators are overexpressed and stimulated by MCP-1. Additionally, MCP-1 alters the physiology of the hepatocytes, promoting immunologic and inflammatory responses beyond regular metabolism. Alcoholism and other factor including abnormal diet stimulate the liver's synthesis of MCP-1, which can result in inflammation in liver. Studies shows how MCP-1' linked to various liver disorders like alcoholic liver disease, liver fibrosis, non-alcoholic fatty liver disease, hepatitis, hepatic steatosis, hepatocellular cancer, primary biliary cirrhosis. MCP-1 not only predicts the onset, progression, and prognosis of the illness, but it is also directly related to the degree and stage of liver inflammation. In this review, we will explore the mechanism and connection between MCP-1's overexpression in liver disorders, further how it can be linked as a therapeutic biomarker in the above scenario.

IFNλ4 has posed a conundrum in human immunology since its discovery in 2013, with its expression linked to complications with viral clearance. While genetic and cellular studies revealed the detrimental effects of IFNλ4 expression, extensive structural and functional characterization has been limited by the inability to express and purify the protein, complicating explanations of its paradoxical behavior. In this work, we report a method for robust production of IFNλ4. We then use yeast surface display to affinity-mature IL10Rβ and solve the 72 kilodalton structures of IFNλ4 (3.26 Å) and IFNλ3 (3.00 Å) in complex with their receptors IFNλR1 and IL10Rβ using cryogenic electron microscopy. Comparison of the structures highlights differences in receptor engagement and reveals a distinct 12-degree rotation in overall receptor geometry, providing a potential mechanistic explanation for differences in cell signaling, downstream gene induction, and antiviral activities. Further, we perform a structural analysis using molecular modeling and simulation to identify a unique region of IFNλ4 that, when replaced, enables secretion of the protein from cells. These findings provide a structural and functional understanding of the IFNλ4 protein and enable future comprehensive studies towards correcting IFNλ4 dysfunction in large populations of affected patients.

Human interferon (IFN) lambda (IFNL, IFN-L or IFN-λ) locus has several functional genetic variants but their role in regulating in vivo gene expression, and whether they associate with antiviral states in healthy individuals, is not clear. In this study, we recruited ∼550 healthy individuals belonging to both sexes, genotyped them for several IFNL genetic variants and measured, by qPCR, the expression of IFNL2/3, IFNL4 and four IFN-stimulated genes (ISGs) (MX1, OAS1, ISG15 and RSAD2) from their peripheral blood mononuclear cells (PBMC) both before and after stimulation with a viral mimic, poly I: C. We also measured secreted levels of several cytokines including IFN-λ1 and IFN-λ3 in poly I:C stimulated PBMCs. We found that males secrete higher levels of IFN-λs than females. The IFNL3/4 genetic variants significantly associated with secreted levels of both IFN-λ1 and IFN-λ3 in opposite directions, only in males. While the IFNL3/4 variants significantly associated with ISG expression either in basal or poly I:C induced or in both states, the direction of effect was opposite for the two sexes, suggesting that sex was a strong effect modifier. We did not see this trend in the association of ISG expression with the IFNL1 polymorphism, rs7247086, whose association with ISG expression and secreted IFN-λ3 levels was seen in females but not in males. Further, expression of several genes was associated with the IFN-λ4 activity-modifying variant rs117648444. However, we neither saw any strong correlation between levels of IFN-λ1/3 and ISG expression, nor did we see any strong evidence of IFNL4 expression that could be responsible for the association between ISG expression and IFNL genetic variants. These results suggest that there are complex interactions involving gender, IFN-λs, IFN-λ genetic variants and antiviral states in humans.

Recent advances in the genetics of metabolic dysfunction-associated steatotic liver disease (MASLD) are gradually revealing the mechanisms underlying the heterogeneity of the disease and have shown promising results in patient stratification. Genetic characterization of the disease has been rapidly developed using genome-wide association studies, exome-wide association studies, phenome-wide association studies, and whole exome sequencing. These advances have been powered by the increase in computational power, the development of new analytical algorithms, including some based on artificial intelligence, and the recruitment of large and well-phenotyped cohorts. This review presents an update on genetic studies that emphasize new biological insights from next-generation sequencing approaches. Additionally, we discuss innovative methods for discovering new genetic loci for MASLD, including rare variants. To comprehensively manage MASLD, it is important to stratify risks. Therefore, we present an update on phenome-wide association study associations, including extreme phenotypes. Additionally, we discuss whether polygenic risk scores and targeted sequencing are ready for clinical use. With particular focus on precision medicine, we introduce concepts such as the interplay between genetics and the environment in modulating genetic risk with lifestyle or standard therapies. A special chapter is dedicated to gene-based therapeutics. The limitations of approved pharmacological approaches are discussed, and the potential of gene-related mechanisms in therapeutic development is reviewed, including the decision to perform genetic testing in patients with MASLD.

Human infectious diseases are unique in that the discovery of their environmental trigger, the microbe, was sufficient to drive the development of extraordinarily effective principles and tools for their prevention or cure. This unique medical prowess has outpaced, and perhaps even hindered, the development of scientific progress of equal magnitude in the biological understanding of infectious diseases. Indeed, the hope kindled by the germ theory of disease was rapidly subdued by the infection enigma, in need of a host solution, when it was realized that most individuals infected with most infectious agents continue to do well. The root causes of disease and death in the unhappy few remained unclear. While canonical approaches in vitro (cellular microbiology), in vivo (animal models), and in natura (clinical studies) analyzed the consequences of infection with a microbe, considered to be the cause of disease, in cells, tissues, or organisms seen as a uniform host, alternative approaches searched for preexisting causes of disease, particularly human genetic and immunological determinants in populations of diverse individuals infected with a trigger microbe.

Texas has the highest HCC rates in the United States, and the greatest burden is among Hispanics. Racial and ethnic disparities in HCC incidence have multiple underpinning factors. We conducted a mediation analysis to examine the role of neighborhood disadvantage (Area Deprivation Index) as a potential mediator of the association between neighborhood race and ethnicity distribution and neighborhood HCC case counts in Texas.

The primary outcome measure was counts of new HCC diagnoses per census tract based on Texas Department of State Health Services Texas Cancer Registry data. The primary exposure of interest was the race and ethnicity-based Index of Concentration at the Extremes (non-Hispanic Black ICE or Hispanic ICE). We assessed Area Deprivation Index as a potential mediator of the association between Black/Hispanic ICE and HCC case counts. We adjusted the analyses for selected census tract characteristics.

We analyzed 4934 census tracts containing 13,632 new HCC diagnoses reported to Texas Cancer Registry between 2016 and 2020. Racial minority (Black/Hispanic ICE)-concentrated neighborhoods had a higher socioeconomic disadvantage. The results of the mediation analyses showed that compared to non-Hispanic White-concentrated census tracts, non-Hispanic Black-concentrated census tracts and Hispanic-concentrated census tracts had higher case counts of HCC (total effects: adjusted case count ratio: 1.03 [95% CI, 1.02-1.04] and adjusted case count ratio: 1.09 [95% CI, 1.08-1.10], respectively). Approximately 48% and 15% of the neighborhood-level disparity in HCC case counts were attributable to neighborhood socioeconomic disadvantage in Black and Hispanic minoritized neighborhoods, respectively.

Neighborhood HCC case counts varied by neighborhood race and ethnicity distribution. The variations were partly explained by neighborhood deprivation, with a stronger effect among Black-concentrated census tracts.

Mutations in SARS-CoV-2 variants of concern (VOCs) have expanded the viral host range beyond primates, and a few other mammals, to mice, affording the opportunity to exploit genetically diverse mouse panels to model the broad spectrum of responses to infection in patient populations. Here we surveyed responses to VOC infection in genetically diverse Collaborative Cross (CC) founder strains. Infection of wild-derived CC founder strains produced a broad range of viral burden, disease susceptibility and survival, whereas most other strains were resistant to disease despite measurable lung viral titers. In particular, CAST/EiJ, a wild-derived strain, developed high lung viral burdens, more severe lung pathology than seen in other CC strains, and a dysregulated cytokine profile resulting in morbidity and mortality. These inbred mouse strains may serve as a valuable platform to evaluate therapeutic countermeasures against severe COVID-19 and other coronavirus pandemics in the future.

Next-generation sequencing (NGS) has transformed pharmacogenomics (PGx), enabling thorough profiling of pharmacogenes using computational methods and advancing personalized medicine. The Thai Pharmacogenomic Database-2 (TPGxD-2) analyzed 948 whole genome sequences, primarily from the Electricity Generating Authority of Thailand (EGAT) cohort. This study is an extension of the previous Thai Pharmacogenomic Database (TPGxD-1) and specifically focused on 26 non-very important pharmacogenes (VIPGx) genes. Variant calling was conducted using Sentieon (version 201808.08) following GATK's best workflow practices. We then annotated variant call format (VCF) files using Golden Helix VarSeq 2.5.0. Star allele analysis was performed with Stargazer v2.0.2, which called star alleles for 22 of 26 non-VIPGx genes. The variant analysis revealed a total of 14,529 variants in 26 non-VIPGx genes, with TBXAS1 had the highest number of variants (27%). Among the 14,529 variants, 2328 were novel (without rsID), with 87 identified as clinically relevant. We also found 56 known PGx variants among the known variants (n = 12,201), with UGT2B7 (19.64%), CYP1B1 (8.9%), SLCO2B1 (8.9%), and POR (8.9%) being the most common. We reported a high frequency of intermediate metabolizers (IMs) in CYP2F1 (34.6%) and CYP4A11 (8.6%), and a high frequency of decreased functional alleles in POR (53.9%) and SLCO1B3 (34.9%) genes. This study enhances our understanding of pharmacogenomic profiling of 26 non-VIPGx genes of notable clinical importance in the Thai population. However, further validation with additional computational and reference genotyping methods is necessary, and novel alleles identified in this study should undergo further orthogonal validation.

Hepatitis E virus (HEV) infections are a major cause of acute viral hepatitis in humans worldwide. In immunocompetent individuals, the majority of HEV infections remain asymptomatic and lead to spontaneous clearance of the virus, and only a minority of individuals with infection (5-16%) experience symptoms of acute viral hepatitis. However, HEV infections can cause up to 30% mortality in pregnant women, become chronic in immunocompromised patients and cause extrahepatic manifestations. A growing body of evidence suggests that the host immune response to infection with different HEV genotypes is a critical determinant of distinct HEV infection outcomes. In this Review, we summarize key components of the innate and adaptive immune responses to HEV, including the underlying immunological mechanisms of HEV associated with acute and chronic liver failure and interactions between T cell and B cell responses. In addition, we discuss the current status of vaccines against HEV and raise outstanding questions regarding the immune responses induced by HEV and treatment of the disease, highlighting areas for future investigation.

Vaccination is a cornerstone of public health, saving millions of lives each year by preventing a variety of infectious diseases. Yet, despite global vaccination efforts, emerging research highlights significant geographical disparities in vaccine efficacy and immunogenicity. These variations underscore the critical interplay between immunological factors and environmental, genetic, and nutritional elements across different populations. Our review article aimed to explore the multifactorial reasons behind geographical variations in vaccine efficacy. Also, this study has shown how important host factors like age, obesity, gender, and genetic diversity, especially within the major histocompatibility complex, are in determining how well a vaccine works. Nutritional status, namely deficiencies in micronutrients such as vitamins and zinc, and lifestyle factors including stress, sleep, alcohol consumption, and physical activity are also shown to have profound effects on vaccine-induced immunity. Importantly, our paper also brought to light the influence of microbial and ecological factors, such as the gut microbiome and environmental pollutants, on the immune system's response to vaccination. The findings emphasize the importance of tailoring vaccination strategies to accommodate the unique immunological landscapes shaped by geographical and societal factors. This tailored approach could enhance vaccine efficacy, reduce disparities in vaccine response, and ultimately contribute to the global fight against infectious diseases.

Elimination of hepatitis C virus (HCV) without the need for medical intervention, known as spontaneous clearance (SC), occurs at a significantly lower rate than in the case of hepatitis B virus infection and only in selected individuals, such as reportedly in Keith Richards, a guitarist of The Rolling Stones. The present paper provides an updated narrative review of the research devoted to the phenomenon in order to identify and discuss the demographic, lifestyle-related, clinical, viral genotype-related, and host genetic factors underpinning the SC occurrence. The body of evidence indicates that the likelihood of SC is decreased in older individuals, men, Black people, HIV-coinfected subjects, and intravenous drug and alcohol users. In turn, HBV coinfection and specific polymorphism of the genes encoding interferon lambda 3 (particularly at rs8099917) and interferon lambda 4 (particularly at rs12979860) and HLA genes increase the odds of SC. Numerous other host-specific genetic factors could be implicated in SC, but the evidence is limited only to certain ethnic groups and often does not account for confounding variables. SC of HCV infection is a complex process arising from a combination of various factors, though a genetic component may play a leading role in some cases. Understanding factors influencing the likelihood of this phenomenon justifies better surveillance of high-risk groups, decreasing health inequities in particular ethnic groups, and may guide the development of a prophylactic vaccine, which at present is not available, or novel therapeutic strategies. Further research is needed to elucidate the exact mechanisms underlying SC and to explore potential interventions that could enhance this natural antiviral response.

The prevalence of HCV infection in Egypt has decreased following the introduction of direct-acting antiviral therapy. However, treatment response is influenced by various factors, particularly host immunogenetics such as IL-28B and FOXP3 polymorphisms. The current study examined the impact of SNPs in the FOXP3 gene promoter region on HCV-infected Egyptian patients, along with SNPs in the IL28B gene.This study involved 99 HCV patients who achieved SVR12 after a 12 week DAA treatment while 63 HCV patients experienced treatment failure. IL28B rs12979860 SNP was identified using real-time PCR, while IL28B rs8099917, FOXP3 rs3761548, and rs2232365 SNPs were analyzed using RFLP-PCR. Serum levels of IL28B and FOXP3 were quantified using ELISA technique in representative samples from both groups. The IL28B rs12979860 T > C (P = 0.013) and FOXP3 rs2232365 A > G polymorphisms (P = 0.008) were found to significantly increase the risk of non-response. Responders had higher IL28B serum levels (P = 0.046) and lower FOXP3 levels (P < 0.001) compared to non-responders. Regression analysis showed an association between IL28B rs12979860 and FOXP3 rs2232365 with treatment response, independent of age and gender. A predictive model was developed with 76.2% sensitivity and 91.9% specificity for estimating DAAs response in HCV patients.Our findings confirmed the IL28B rs12979860 T > C and FOXP3 rs2232365 A > G polymorphisms significantly affect DAA treatment response in HCV Egyptian patients. Lower levels of IL-28B along with higher levels of FOXP3 are linked to poor response. Our results may lead to new insights into DAA responsiveness contributing to personalized medicine and improving therapeutic decision-making for HCV patients.

Hepatitis C virus (HCV) reinfection after curative treatment remains a concern for people who inject drugs.

To assess the incidence of HCV reinfection and associated risk factors.

This cohort study is a secondary analysis of a randomized clinical trial that was conducted across opioid treatment programs and community health centers in the US between September 2016 and August 2018. The current analyses were performed in March 2022. People who inject drugs who achieved sustained virologic response (SVR) were followed for up to 42 months.

Patients were randomly assigned to receive modified directly observed therapy or patient navigation.

The primary outcome was rate of HCV reinfection. Change in reinfection rates over time was assessed using a Poisson regression model.

A total of 415 participants (mean [SD] age, 44.7 [11.5] years; 302 male [72.8%]) achieved a SVR and had 1 or more post-SVR assessments for HCV RNA. Overall, 302 (72.8%) reported recent injection drug use, 192 (46.3%) were living in unstable housing, and 313 (75.4%) had received recent methadone or buprenorphine for opioid use disorder. The overall reinfection rate was 11.4 per 100 person-years at risk (95% CI, 8.7-14.7 per 100 person-years at risk) over 518 person-years of follow-up. Reinfection rates varied significantly across sites, ranging from 2.9 per 100 person-years at risk (95% CI, 0.1-16.3 per 100 person-years) to 25.2 per 100 person-years at risk (95% CI, 15.6-38.5 per 100 person-years at risk) (P = .006). There was a significant decrease in incident reinfection with increasing post-SVR follow-up (weeks 0-24, 15.5 per 100 person-years; 95% CI, 10.3-22.3 per 100 person-years; weeks 73-144, 4.3 per 100 person-years; 95% CI, 0.9-12.5 per 100 person-years; P = .008). Reinfection rates were lower for participants aged 40 years or older than for younger participants (adjusted incidence rate ratio, 0.32; 95% CI, 0.18-0.57) and for participants for whom methamphetamine was not detected in urinary drug screening compared with participants for whom methamphetamine was detected (adjusted incidence rate ratio, 0.41; 95% CI, 0.21-0.82). Participants who reported injection drug use within the preceding 3 months had higher risk of reinfection than those who did not have recent injection drug use (adjusted incidence rate ratio, 3.33; 95% CI, 1.86-5.97).

In this cohort study of people who injected drugs and were treated for HCV infection in community settings, reinfection was high in the period immediately after SVR but decreased significantly over time. These findings highlight the importance of early intervention to prevent reinfection.

ClinicalTrials.gov Identifier: NCT02824640.

Mutations in SARS-CoV-2 variants of concern (VOCs) have expanded the viral host range beyond primates, and a limited range of other mammals, to mice, affording the opportunity to exploit genetically diverse mouse panels to model the broad range of responses to infection in patient populations. Here we surveyed responses to VOC infection in genetically diverse Collaborative Cross (CC) founder strains. Infection of wild-derived CC founder strains produced a broad range of viral burden, disease susceptibility and survival, whereas most other strains were resistant to disease despite measurable lung viral titers. In particular, CAST/EiJ, a wild-derived strain, developed high lung viral burdens, more severe lung pathology than seen in other CC strains, and a dysregulated cytokine profile resulting in morbidity and mortality. These inbred mouse strains may serve as a valuable platform to evaluate therapeutic countermeasures against severe COVID-19 and other coronavirus pandemics in the future.

Models are often employed to integrate knowledge about epidemics across scales and simulate disease dynamics. While these approaches have played a central role in studying the mechanics underlying epidemics, we lack ways to reliably predict how the relationship between virulence (the harm to hosts caused by an infection) and transmission will evolve in certain virus-host contexts. In this study, we invoke evolutionary invasion analysis-a method used to identify the evolution of uninvadable strategies in dynamical systems-to examine how the virulence-transmission dichotomy can evolve in models of virus infections defined by different natural histories. We reveal peculiar patterns of virulence evolution between epidemics with different disease natural histories (SARS-CoV-2 and hepatitis C virus). We discuss the findings with regards to the public health implications of predicting virus evolution, and in broader theoretical canon involving virulence evolution in host-parasite systems.

Coronavirus (CoV) cause considerable morbidity and mortality in humans and other mammals, as evidenced by the emergence of Severe Acute Respiratory CoV (SARS-CoV) in 2003, Middle East Respiratory CoV (MERS-CoV) in 2012, and SARS-CoV-2 in 2019. Although poorly characterized, natural genetic variation in human and other mammals modulate virus pathogenesis, as reflected by the spectrum of clinical outcomes ranging from asymptomatic infections to lethal disease. Using multiple human epidemic and zoonotic Sarbecoviruses, coupled with murine Collaborative Cross genetic reference populations, we identify several dozen quantitative trait loci that regulate SARS-like group-2B CoV pathogenesis and replication. Under a Chr4 QTL, we deleted a candidate interferon stimulated gene, Trim14 which resulted in enhanced SARS-CoV titers and clinical disease, suggesting an antiviral role during infection. Importantly, about 60 % of the murine QTL encode susceptibility genes identified as priority candidates from human genome-wide association studies (GWAS) studies after SARS-CoV-2 infection, suggesting that similar selective forces have targeted analogous genes and pathways to regulate Sarbecovirus disease across diverse mammalian hosts. These studies provide an experimental platform in rodents to investigate the molecular-genetic mechanisms by which potential cross mammalian susceptibility loci and genes regulate type-specific and cross-SARS-like group 2B CoV replication, immunity, and pathogenesis in rodent models. Our study also provides a paradigm for identifying susceptibility loci for other highly heterogeneous and virulent viruses that sporadically emerge from zoonotic reservoirs to plague human and animal populations.

Mutations in the non-structural protein regions of hepatitis C virus (HCV) are a cause of a non-sustained virological response (SVR) to treatment with direct-acting antivirals (DAAs) for chronic hepatitis; however, there are non-SVR cases without these mutations. In this study, we examined immune cell profiles in peripheral blood before and after ombitasvir/paritaprevir/ritonavir treatment and screened for genes that could be used to predict the therapeutic effects of DAAs. Fluorescence-activated cell sorting analysis indicated that the median frequencies of programmed cell death-1-positive (PD-1+) effector regulatory T cells (eTregs), PD-1+CD8+ T cells, and PD-1+Helper T cells were decreased significantly in SVR cases, but without significant changes in non-SVR cases. The frequency of PD-1+ naïve Tregs was significantly higher in the SVR group than in the non-SVR group before and after treatment. Similar results were found in patients treated with other DAAs (e.g., daclatasvir plus asunaprevir) and supported an immune response after HCV therapy. RNA-sequencing analysis indicated a significant increase in the expression of genes associated with the immune response in the SVR group, while genes related to intracellular and extracellular signal transduction were highly expressed in the non-SVR group. Therefore, we searched for genes associated with PD-1+ eTregs and CD8+ T cells that were significantly different between the SVR and non-SVR groups and found that T-box transcription factor 21 was associated with the non-SVR state. These results indicate that PD-1-related signaling pathways are associated with a non-SVR mechanism after DAAs treatment separate from mutation-related drug resistance.

The essential and redundant functions of human type I and II interferons (IFNs) have been delineated over the last three decades by studies of patients with inborn errors of immunity or their autoimmune phenocopies, but much less is known about type III IFNs. Patients with cells that do not respond to type III IFNs due to inherited IL10RB deficiency display no overt viral disease, and their inflammatory disease phenotypes can be explained by defective signaling via other interleukine10RB-dependent pathways. Moreover, patients with inherited deficiencies of interferon-stimulated gene factor 3 (ISGF-3) (STAT1, STAT2, IRF9) present viral diseases also seen in patients with inherited deficiencies of the type I IFN receptor (IFNAR1/2). Finally, patients with autoantibodies neutralizing type III IFNs have no obvious predisposition to viral disease. Current findings thus suggest that type III IFNs are largely redundant in humans. The essential functions of human type III IFNs, particularly in antiviral defenses, remain to be discovered.

In humans, the interindividual variability of clinical outcome following exposure to a microorganism is immense, ranging from silent infection to life-threatening disease. Age-specific immune responses partially account for the high incidence of infection during the first 28 days of life and the related high mortality at population level. However, the occurrence of life-threatening disease in individual newborns remains unexplained. By contrast, inborn errors of immunity and their immune phenocopies are increasingly being discovered in children and adults with life-threatening viral, bacterial, mycobacterial and fungal infections. There is a need for convergence between the fields of neonatal immunology, with its in-depth population-wide characterization of newborn-specific immune responses, and clinical immunology, with its investigations of infections in patients at the cellular and molecular levels, to facilitate identification of the mechanisms of susceptibility to infection in individual newborns and the design of novel preventive and therapeutic strategies.

Type III interferons (IFN), also called as lambda IFNs (IFN-λs), are antiviral and immunomodulatory cytokines that are evolutionarily important in humans. Given their central roles in innate immunity, they could be influencing other aspects of human biology. This study aimed to examine the association of genetic variants that control the expression and/or activity of IFN-λ3 and IFN-λ4 with multiple phenotypes in blood profiles of healthy individuals.

In a cohort of about 550 self-declared healthy individuals, after applying several exclusion criteria to determine their health status, we measured 30 blood parameters, including cellular, biochemical, and metabolic profiles. We genotyped them at rs12979860 and rs28416813 using competitive allele-specific PCR assays and tested their association with the blood profiles under dominant and recessive models for the minor allele. IFN-λ4 variants rs368234815 and rs117648444 were also genotyped or inferred.

We saw no association in the combined cohort under either of the models for any of the phenotypes. When we stratified the cohort based on gender, we saw a significant association only in males with monocyte (p = 1 × 10-3 ) and SGOT (p = 7 × 10-3 ) levels under the dominant model and with uric acid levels (p = 0.01) under the recessive model. When we tested the IFN-λ4 activity modifying variant within groupings based on absence or presence of one or two copies of IFN-λ4 and on different activity levels of IFN-λ4, we found significant (p < 0.05) association with several phenotypes like monocyte, triglyceride, VLDL, ALP, and uric acid levels, only in males. All the above significant associations did not show any confounding when we tested for the same with up to ten different demographic and lifestyle variables.

These results show that lambda interferons can have pleiotropic effects. However, gender seems to be an effect modifier, with males being more sensitive than females to the effect.

Studying host-pathogen interactions at a molecular level has always been technically challenging. Identifying the different biochemical and genetic pathways involved in the different stages of infection traditionally require complex molecular biology tools and often the use of costly animal models. In this chapter, we illustrate a complementary approach to address host-pathogen interactions, taking advantage of the natural interindividual genetic diversity. The application of genetic association studies allows us to identify alleles involved in infection progression or resistance. Thus, this strategy may be useful to unravel new molecular pathways underlying host-pathogen interactions. Here we present the general steps that might be followed to plan, execute, and analyze a population-based study in order to identify genetic variants affecting human exposition to pathogens.

In the US, the prevalence of hepatitis C virus (HCV) is 1.8% among people who are Black and 0.8% among people who are not Black. Mortality rates due to HCV are 5.01/100 000 among people who are Black and 2.98/100 000 among people who are White.

While people of all races and ethnicities experienced increased rates of incident HCV between 2015 and 2021, Black individuals experienced the largest percentage increase of 0.3 to 1.4/100 000 (367%) compared with 1.8 to 2.7/100 000 among American Indian/Alaska Native (50%), 0.3 to 0.9/100 000 among Hispanic (200%), and 0.9 to 1.6/100 000 among White (78%) populations. Among 47 687 persons diagnosed with HCV in 2019-2020, including 37 877 (79%) covered by Medicaid (7666 Black and 24 374 White individuals), 23.5% of Black people and 23.7% of White people with Medicaid insurance initiated HCV treatment. Strategies to increase HCV screening include electronic health record prompts for universal HCV screening, which increased screening tests from 2052/month to 4169/month in an outpatient setting. Awareness of HCV status can be increased through point-of-care testing in community-based settings, which was associated with increased likelihood of receiving HCV test results compared with referral for testing off-site (69% on-site vs 19% off-site, P < .001). Access to HCV care can be facilitated by patient navigation, in which an individual is assigned to work with a patient to help them access care and treatments; this was associated with greater likelihood of HCV care access (odds ratio, 3.7 [95% CI, 2.9-4.8]) and treatment initiation within 6 months (odds ratio, 3.2 [95% CI, 2.3-4.2]) in a public health system providing health care to individuals regardless of their insurance status or ability to pay compared with usual care. Eliminating Medicaid's HCV treatment restrictions, including removal of a requirement for advanced fibrosis or a specialist prescriber, was associated with increased treatment rates from 2.4 persons per month to 72.3 persons per month in a retrospective study of 10 336 adults with HCV with no significant difference by race (526/1388 [37.8%] for Black vs 2706/8277 [32.6%] for White patients; adjusted odds ratio, 1.02 [95% CI, 0.8-1.3]).

In the US, the prevalence of HCV is higher in people who are Black than in people who are not Black. Point-of-care HCV tests, patient navigation, electronic health record prompts, and unrestricted access to HCV treatment in community-based settings have potential to increase diagnosis and treatment of HCV and improve outcomes in people who are Black.

The allelic discrimination of IFNL3-(rs12979860 C > T) polymorphism reveals ambiguous associations with the effectiveness of oral HCV treatment. Solitary intra peripheral-blood-mononuclear-cells (PBMCs) HCV-RNA antisense-strands are independently detected in naïve and experienced cases regardless of viremia or hepatic-parenchymal alterations. We examined the frequencies of IFNL3-genetic variants with chronic-HCV-induced liver changes during the sustained virologic response (SVR) by evaluating the PBMCs- HCV-PCR after oral antiviral therapy. Methods: Twelve weeks after finishing oral antiviral therapy, the effects of IFNL3-genetic variants were evaluated in three groups of patients: Group-I (n = 25) showed HCV-RNA negativity in both serum and PBMCs-, group II (n = 52) showed positivity of HCV-RNA in PBMCs, and group-III (n = 25) had positive HCV-RNA in serum. The genetic variants of the IFNL3-gene were estimated for all the enrolled cases and correlated with their hepatic image changes. Results: IFNL3-(rs12979860) genotyping in post-direct acting antivirals (DAAs) SVR and HCV-relapse revealed: a) high frequency of CC-genotype and C-allele in group I compared to group II (P < 0.005) and group III(P ≤ 0.05) when hepatic-parenchyma looks normal by ultrasound b) frequent CT-genotype and T-allele in group II compared with I(P < 0.01) and III(P < 0.05) when liver tissues are bright (early cirrhotic-changes) c) frequent TT-genotype and T-allele in group III relative to I (P < 0.05) and II (P ≤ 0.08) when liver-tissues appear coarse by ultrasound. Conclusion: Outcomes of HCV treatment depend on host IFNL3-gene polymorphism and hepatic-parenchymal changes. A high frequency of wild-CC-genotype and C-allele is observed in patients with normal hepatic parenchyma and that achieved SVR. Solitary relapse in PBMCs occurs on increasing CT-genotype frequency when liver tissues are bright. Serologic relapse is detected when TT-genotype and T-allele are dominant in association with the cirrhotic liver. Therefore, IFNL3-gene-SNP analysis as a genetic predictor in relation to ultra-sonographic hepatic-parenchymal changes could be valuable for selecting the patients with the highest priority for treatment.

Our findings define a novel role for ZIKV-induced TTP expression in regulating IFNβ/IFNλ production in primary hBMECs and Sertoli cells. These cells comprise key physiological barriers subverted by ZIKV to access brain and testicular compartments and serve as reservoirs for persistent replication and dissemination. We demonstrate for the first time that the ARE-binding protein TTP is virally induced and post-transcriptionally regulates IFNβ/IFNλ secretion. In ZIKV-infected hBMEC and Sertoli cells, TTP knockout increased IFNβ/IFNλ secretion, while TTP expression blocked IFNβ/IFNλ secretion. The TTP-directed blockade of IFN secretion permits ZIKV spread and persistence in hBMECs and Sertoli cells and may similarly augment ZIKV spread across IFNλ-protected placental barriers. Our work highlights the importance of post-transcriptional ZIKV regulation of IFN expression and secretion in cells that regulate viral access to protected compartments and defines a novel mechanism of ZIKV-regulated IFN responses which may facilitate neurovirulence and sexual transmission.

Hepatitis C virus (HCV) infection is a worldwide public health problem. Chronic infection with HCV can lead to liver cirrhosis or cancer. Although some immune-competent individuals can clear the virus, others develop chronic HCV disease due to viral mutations or an impaired immune response. IFNs type I and III and the signal transduction induced by them are essential for a proper antiviral effect. Research on the viral cycle and immune escape mechanisms has formed the basis of therapeutic strategies to achieve a sustained virological response (SVR). The first therapies were based on IFNα; then, IFNα plus ribavirin (IFN-RBV); and then, pegylated-IFNα-RBV (PEGIFNα-RIV) to improve cytokine pharmacokinetics. However, the maximum SVR was 60%, and several significant side effects were observed, decreasing patients' treatment adherence. The development of direct-acting antivirals (DAAs) significantly enhanced the SVR (>90%), and the compounds were able to inhibit HCV replication without significant side effects, even in paediatric populations. The management of coinfected HBV-HCV and HCV-HIV patients has also improved based on DAA and PEG-IFNα-RBV (HBV-HCV). CD4 cells are crucial for an effective antiviral response. The IFNλ3, IL28B, TNF-α, IL-10, TLR-3, and TLR-9 gene polymorphisms are involved in viral clearance, therapeutic responses, and hepatic pathologies. Future research should focus on searching for strategies to circumvent resistance-associated substitution (RAS) to DAAs, develop new therapeutic schemes for different medical conditions, including organ transplant, and develop vaccines for long-lasting cellular and humoral responses with cross-protection against different HCV genotypes. The goal is to minimise the probability of HCV infection, HCV chronicity and hepatic carcinoma.