Hepatitis C virus (HCV) infection is the most common blood borne infection in the U.S. with estimates of 4 million HCV-infected individuals in the U.S. and 170 million worldwide1. The majority (70%–80%) of HCV infections persist and about 30% of individuals with persistent infection develop chronic liver disease, including cirrhosis and hepatocellular carcinoma2. Epidemiological, viral, and host factors have been associated with the differences in HCV clearance or persistence and studies have demonstrated that a strong host immune response against HCV favors viral clearance3,4. Thus, variation in genes involved in the immune response may contribute to the ability to clear the virus. In a recent genome-wide association study, a single nucleotide polymorphism (rs12979860) 3kb upstream of the IL28B gene, which encodes the type III interferon IFN-λ3, was shown to associate strongly with more than a 2-fold difference in response to HCV drug treatment5. To determine the potential effect of rs12979860 variation on outcome to HCV infection in a natural history setting, we genotyped this variant in HCV cohorts comprised of individuals who spontaneously cleared the virus (N = 388) or had persistent infection (N = 620). We show that the C/C genotype strongly enhances resolution of HCV infection amongst individuals of both European and African ancestry (European: OR = 0.38, p = 10−7; African: OR = 0.32, p = 10−4; combined: OR = 0.33, p <10−12). To date, this is the strongest and most significant genetic effect associated with natural clearance of HCV, and these results implicate a primary role for IL28B in resolution of HCV infection.

Background Blood donors are at risk of iron deficiency. We evaluated the effects of blood donation intensity on iron and hemoglobin in a prospective study. Methods Four cohorts of frequent and first time or reactivated blood donors (no donation in 2 years), female and male, totaling 2425 were characterized and followed as they donated blood frequently. At enrollment and the final visit, ferritin, soluble transferrin receptor (sTfR), and hemoglobin were determined. Models to predict iron deficiency and hemoglobin deferral were developed. Iron depletion was defined at two levels: Iron Deficient Erythropoiesis (IDE) [log (soluble transferrin receptor/ferritin ≥ 2.07)] and Absent Iron Stores (AIS) (ferritin < 12 ng/mL). Results Among returning female first time/reactivated donors, 20% and 51% had AIS and IDE at their final visit, respectively; corresponding proportions for males were 8% and 20%. Among female frequent donors who returned, 27% and 62% had AIS and IDE, respectively, while corresponding proportions for males were 18% and 47%. Predictors of IDE and/or AIS included a higher frequency of blood donation in the last 2 years, a shorter interdonation interval, and being female and young; conversely, taking iron supplements reduced the risk of iron depletion. Predictors of hemoglobin deferral included female gender, Black race and a shorter interdonation interval. Conclusions There is a high prevalence of iron depletion in frequent blood donors. Increasing the interdonation interval would reduce the prevalence of iron depletion and hemoglobin deferral. Alternatively, replacement with iron supplements may allow frequent donation without the adverse outcome of iron depletion.

Background Hepatitis C virus (HCV) infection, clearance and reinfection are best studied in injection drug users (IDU) who have the highest incidence and are representative of most infections. Methods A prospective cohort of HCV negative young IDU was followed from 2000 to 2007, to identify acute and incident HCV and prospectively study infection outcomes. Results Among 1,191 young IDU screened, 731 (61.4%) were HCV negative, and 520 (71.1%) were enrolled into follow-up. Cumulative HCV incidence was 26.7 per 100 person years of observation (PYO) (95% CI, 21.5, 31.6). 95 (70.4%) of 135 acute/incident HCV infections were followed; 21% cleared HCV. Women had a significantly higher incidence of viral clearance compared to men (age-adjusted relative hazard 2.91, 95% CI, 1.68, 5.03) and also showed a significantly faster rate of early HCV viremia decline. Estimated reinfection rate was 24.6 per 100 PYO (95% CI, 11.7, 51.6). Among seven individuals, multiple episodes of HCV reinfection and re-clearance were observed. Conclusions In this large sample of young IDU, females show demonstrative differences in their rates of viral clearance and kinetics of early viral decline. Recurring reinfection and re-clearance suggest possible protection against persistent infection. These results should inform HCV clinical care and vaccine development.

The present study examined reasons for the high incidence of hepatitis C virus (HCV) infection among young injection drug users (IDUs). IDUs <30 years old who tested negative for HCV antibody were enrolled in a prospective cohort. Risk factors for seroconversion were examined using time-dependent regression analyses: 48 of 195 IDUs seroconverted to HCV, for an incidence rate of 25.1/100 person-years (95% confidence interval, 18.7-32.9/100 person-years). Independent risk factors included sharing needles with an HCV-infected sex partner (borderline statistical significance, P=.11) or a person who was not a sex partner, sharing nonsterile drug-preparation equipment, pooling money with another IDU to buy drugs, and exchanging sex for money. Ubiquitous behaviors among young IDUs, such as the forming of injecting or sexual partnerships and consequent sharing of needles and drug preparation equipment, are risk factors for HCV. Interventions to reduce HCV transmission must recognize the importance of relationships on injecting risk.

West Nile virus (WNV) causes asymptomatic infection in most humans, but for undefined reasons, approximately 20% of immunocompetent individuals develop West Nile fever, a potentially debilitating febrile illness, and approximately 1% develop neuroinvasive disease syndromes. Notably, since its emergence in 1999, WNV has become the leading cause of epidemic viral encephalitis in North America. We hypothesized that CD4 + Tregs might be differentially regulated in subjects with symptomatic compared with those with asymptomatic WNV infection. Here, we show that in 32 blood donors with acute WNV infection, Tregs expanded significantly in the 3 months after index (RNA + ) donations in all subjects. Symptomatic donors exhibited lower Treg frequencies from 2 weeks through 1 year after index donation yet did not show differences in systemic T cell or generalized inflammatory responses. In parallel prospective experimental studies, symptomatic WNV-infected mice also developed lower Treg frequencies compared with asymptomatic mice at 2 weeks after infection. Moreover, Treg-deficient mice developed lethal WNV infection at a higher rate than controls. Together, these results suggest that higher levels of peripheral Tregs after infection protect against severe WNV disease in immunocompetent animals and humans.

Background Hepatitis C virus (HCV) infections occur worldwide and either spontaneously resolve or persist and markedly increase the person’s lifetime risk of cirrhosis and hepatocellular carcinoma. Although HCV persistence occurs more often in persons of African ancestry and in persons with a genetic variant near IL28B, the genetic basis is not well understood. Objective To evaluate the host genetic basis for spontaneous resolution of HCV infection. Design Two-stage genome wide association study (GWAS). Setting 13 international multicenter study sites. Patients 919 individuals with serum HCV antibodies but no HCV RNA (spontaneous resolution) and 1482 individuals with serum HCV antibodies and RNA (persistence). Measurements Frequencies of 792,721 SNPs. Results Differences in allele frequencies between persons with spontaneous resolution and persistence were identified on chromosomes 19q13.13 and 6p21.32. On chromosome 19, allele frequency differences localized near IL28B and included rs12979860 (overall per-allele OR = 0.45, P = 2.17 × 10−30) and 10 additional SNPs spanning 55,000 bases. On chromosome 6, allele frequency differences localized near genes for class II human leukocyte antigens (HLA) and included rs4273729 (overall per-allele OR= 0.59, P = 1.71 × 10−16) near DQB1*03:01 and an additional 116 SNPs spanning 1,090,000 base pairs. The associations in chromosomes 19 and 6 were independent, additive, and explain an estimated 14.9% (95% CI: 8.5–22.6%) of the variation in HCV resolution in those of European-Ancestry, and 15.8% (95% CI:4.4–31.0%) in individuals of African-Ancestry. Replication of the chromosome 6 SNP, rs4272729 in an additional 746 individuals confirmed the findings (p=0.015). Limitations Epigenetic effects were not studied. Conclusions IL28B and HLA class II are independently associated with spontaneous resolution of HCV infection and SNPs marking IL28B and DQB1*03:01 may explain ~15% of spontaneous resolution of HCV infection.

IgM and IgG develop rapidly after viremia and before RNA levels become undetectable, which occurred a mean of 13.2 days after the index donation among donors in this study. WNV RNA detection by replicate TMA rarely persists for >40 days after the index donation and is accompanied by WNV-specific neutralizing antibody, consistent with an absence of WNV transmission via transfusion of seropositive blood components.

Dengue viremia rates among asymptomatic blood donors ranged from 0.30 percent in Honduras to 0.04 percent in Brazil. Future studies are needed to establish rates of transfusion transmission by viremic donations and clinical consequences in recipients.