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1.  Seroprevalence of Hepatitis C Virus and Hepatitis B Virus Among San Francisco Injection Drug Users, 1998 to 2000 
Hepatology (Baltimore, Md.)  2007;46(3):666-671.
Previous studies suggest that most injection drug users (IDUs) become infected with hepatitis C virus (HCV) and hepatitis B virus (HBV) soon after initiating drug use. The Urban Health Study (UHS) recruited serial cross-sections of IDUs in the San Francisco Bay area from 1986 to 2005. In the current study, we determined the prevalence of antibody to HCV and HBV (core) among UHS participants during 1998 to 2000. To examine whether the time from onset of injection to acquisition of viral hepatitis has increased, we also compared the findings among recent (<10 years) initiates to drug use who participated during 1998-2000 with those who participated in 1987. Of 2,296 IDUs who participated during 1998-2000, 91.1% had antibody to HCV and 80.5% to HBV. The number of years a person had injected drugs strongly predicted infection with either virus (Ptrend < 0.0001). HCV seroprevalence among recent initiates in 1998-2000, by years of injection drug use, was: ≤ 2, 46.8%; 3 to 5, 72.4%; 6 to 9, 71.3%. By comparison, HCV seroprevalence among 1987 participants was: ≤ 2 years, 75.9%; 3 to 5, 85.7%; 6 to 9, 91.1% (P < 0.0001). A consistent pattern was observed for HBV (P < 0.0001), and these findings were not explained by demographic differences between 1987 and 1998-2000 participants. During 1987, however, 58.7% of recent initiates had shared syringes within the past 30 days compared with 33.6% during 1998-2000 (P < 0.0001).
Conclusion
HCV and HBV seroprevalence among newer initiates to injection drug use in the San Francisco Bay area decreased markedly between 1987 and 1998-2000. This decrease coincided with the implementation of prevention activities among this population.
doi:10.1002/hep.21765
PMCID: PMC4751875  PMID: 17657818
2.  The Inverse Relationship between Chronic HBV and HCV Infections among Injection Drug Users is Associated with Decades of Age and Drug Use 
Journal of viral hepatitis  2008;15(9):690-698.
Summary
Infection with hepatitis C virus (HCV) may suppress co-infection with HBV during acute or chronic HBV infection. We examined relationships between HBV infection, HCV infection and other factors among injection drug users (IDUs) with antibodies to both viruses. Participants enrolled in a cross-sectional study during 1998–2000 were considered to have been infected with HBV if they had core antibody, to be chronically infected if they had HBV surface antigen (HBsAg), to have been infected with HCV if they had HCV antibody, and to be chronically infected if they had HCV RNA. Among 1,694 participants with antibody to both viruses, HBsAg prevalence decreased with increasing age among those positive for HCV RNA [from 4.55% in those 18–29 years to 1.03% in those ≥ 50 years old (ptrend=0.02)], but not among those who were negative for HCV RNA. Chronic HBV infection was less common overall among those with chronic HCV infection (odds ratio [OR], 0.25; p<0.0001), but this inverse relationship was much stronger in the oldest (> 50 years; OR= 0.15) than the youngest (18–29 years; OR=0.81) participants (ptrend=0.03). Similar results were obtained when duration of injection drug use was substituted for age (ptrend= 0.05). Among IDUs who have acquired both HBV and HCV, chronic HBV infection is much less common among those with chronic HCV infection, but this inverse relationship increases markedly with increasing years of age and injection drug use. Co-infection with HCV may enhance the resolution of HBsAg during the chronic phases of these infections.
doi:10.1111/j.1365-2893.2008.01005.x
PMCID: PMC4751881  PMID: 18507757
epidemiology; hepatitis B virus; hepatitis C virus; injection drug use; United States; viral suppression
4.  Subgroup Differences in Response to 8 Weeks of Ledipasvir/Sofosbuvir for Chronic Hepatitis C 
Open Forum Infectious Diseases  2014;1(3):ofu110.
Treatment of hepatitis C virus (HCV) infection with ledipasvir/sofosbuvir promises tremendous benefits, but high cost may impede implementation of this regimen. Subgroups with excellent response to 8 weeks of treatment might respond to a shorter course. In ION-3, 423 previously untreated HCV genotype 1-infected patients without cirrhosis had outcome data after receiving ledipasvir/sofosbuvir for 8 weeks. After reanalyzing published ION-3 data, we found that sustained virologic response (SVR) rates varied significantly by gender (P = .002) and rs12979860 genotype (Ptrend = .03), exceeding 98% in women and rs12979860-CC individuals. The very high SVR rates in these subgroups suggest that these factors might be considered in selecting patients to receive 8 weeks of ledipasvir/sofosbuvir and support shorter trials of this regimen in selected patients.
doi:10.1093/ofid/ofu110
PMCID: PMC4324232  PMID: 25734178
clinical trial; cost-effectiveness; direct-acting antiviral agents; gender; hepatitis C virus; IFNL4
5.  IFN-λ4: The Paradoxical New Member of the Interferon Lambda Family 
Interferons (IFNs) are generally considered antiviral cytokines, yet the newly discovered IFN-λ4 is linked with the failure to clear hepatitis C virus (HCV) infection either spontaneously or in response to treatment. IFN-λ4 can be generated only by individuals who carry the IFNL4-ΔG allele (rs368234815), which is the strongest known host factor for predicting clearance of HCV. The ancestral IFNL4-ΔG allele is the major variant in Africans while the minor variant in Asians, suggesting very strong negative genetic selection for this allele—most likely driven by an infectious agent other than HCV. IFN-λ4 most closely resembles IFN-λ3, but these proteins share only 29% amino-acid identity, and, in contrast to IFN-λ3, IFN-λ4 is only weakly secreted. Nevertheless, IFN-λ4 signals through the IFN-λ receptor complex and induces expression of IFN-stimulated genes via the Janus kinase-signal transducer and activator of transcription signaling pathway. Although the IFNL4-ΔG variant is strongly associated with the failure to clear HCV infection, HCV-infected patients who carry this allele have lower baseline HCV RNA levels in the absence of treatment. Resolving the paradoxical functions of IFN-λ4, which appears to induce antiviral activity yet impair effective clearance of HCV, may yield critical new insights into the immunologic response to HCV infection and IFN biology.
doi:10.1089/jir.2013.0136
PMCID: PMC4217005  PMID: 24786669
6.  Interferon Lambda 4 Genotype Is Not Associated with Recurrence of Oral or Genital Herpes 
PLoS ONE  2015;10(10):e0138827.
IFNL4-ΔG/TT (rs368234815) genotype is associated with hepatitis C virus clearance and may play a role in other infections. IFN-λ4 protein is generated only in individuals who carry the IFNL4-ΔG allele. The IFNL4 rs12979860-T allele, which is in strong linkage disequilibrium with IFNL4-ΔG, was recently reported to be associated with more frequent and severe oral herpes episodes. We investigated the association of IFNL4-ΔG/TT with herpes simplex virus (HSV)-related outcomes among 2,192 African American and European American participants in the Women’s Interagency HIV Study (WIHS). WIHS is a prospective cohort study of human immunodeficiency virus (HIV)–infected and at-risk women that began in 1994. This report includes follow-up through 2013. Available data included: HSV–1 and HSV–2 antibodies at study entry; bi-annually ascertained episodes of (self-reported) oral herpes, (self-reported) genital sores and (clinician-observed) genital ulcers; HSV–2 DNA in cervicovaginal lavage (CVL) specimens. IFNL4-ΔG/TT genotyping was determined by TaqMan. We compared women with IFNL4-ΔG/ΔG or IFNL4-TT/ΔG genotypes (i.e., IFNL4-ΔG carriers) to those with the IFNL4-TT/TT genotype, adjusting for age, race and HIV status. For outcomes with repeated measurements, the adjusted odds ratio (aOR), 95% confidence interval [CI] and p-value were determined using a generalized estimating equations approach. Median participant age at enrollment was 36 years; 81% were African American, 74% were HIV-infected. Among 1,431 participants tested for antibodies, 72.8% were positive for HSV–1 and 79.0% were positive for HSV–2. We observed no association between IFNL4-ΔG/TT genotype and any outcome: HSV–1 or HSV–2 antibody prevalence (p>0.1, all comparisons); oral herpes (aOR, 1.2; p = 0.35); genital sores (aOR, 1.0; p = 0.71); genital ulcers (aOR, 1.1; p = 0.53); detectable HSV–2 DNA in CVL (N = 322; aOR, 0.71; p = 0.49); HSV–2 DNA level (p = 0.68). In this large prospective study, IFNL4-ΔG/TT genotype was not associated with HSV-related outcomes, including episodes of oral or genital herpes.
doi:10.1371/journal.pone.0138827
PMCID: PMC4592222  PMID: 26431156
7.  IFNL4-ΔG Genotype Is Associated With Slower Viral Clearance in Hepatitis C, Genotype-1 Patients Treated With Sofosbuvir and Ribavirin 
The Journal of Infectious Diseases  2013;209(11):1700-1704.
Response to pegylated interferon-alpha and ribavirin (IFN-α/RBV) treatment for chronic hepatitis C virus (HCV) infection is influenced by host genetic factors, but their role for IFN-α–free, direct-acting antiviral (DAA) regimens is unclear. An exonic deletion allele (IFNL4-ΔG) bolsters the established association with IFN-α/RBV therapy treatment outcome of another IFNL4 variant, rs12979860, which is located upstream of IFNL3 (IL28B). We report that in patients treated with the DAA sofosbuvir along with RBV, IFNL4-ΔG is associated with slower early viral decay, due to slower loss of free virus (P = .039) and decreased drug efficacy (P = .048), suggesting functional relevance of IFN-λ4 in IFN-α–free DAA therapies.
doi:10.1093/infdis/jit827
PMCID: PMC4017364  PMID: 24367041
viral kinetics; pharmacokinetics; IL28B; IFNL4; haplotype; SVR; hepatitis C virus; DAA therapy; relapse
9.  A variant upstream of IFNL3 (IL28B) creating a novel interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus 
Nature genetics  2013;45(2):164-171.
SUMMARY
Chronic infection with hepatitis C virus (HCV) is a common cause of liver cirrhosis and cancer. We performed RNA-sequencing in primary human hepatocytes activated with synthetic dsRNA to mimic HCV infection. Upstream of IFNL3 (IL28B) on chromosome 19q13.13, we discovered a novel, transiently induced region that harbors dinucleotide variant ss469415590 (TT/ΔG), which is in high linkage disequilibrium with rs12979860, a genetic marker strongly associated with HCV clearance. ss469415590-ΔG is a frame-shift variant that creates a novel primate-specific gene, designated interferon lambda 4 (IFNL4), which encodes a protein of moderate similarity with IFNL3. Compared to rs12979860, ss469415590 is more strongly associated with HCV clearance in individuals of African ancestry, whereas it provides comparable information in Europeans and Asians. Transient over-expression of IFNL4 in a hepatoma cell line induced STAT1/STAT2 phosphorylation and expression of interferon-stimulated genes. Our findings provide new insights into the genetic regulation of HCV clearance and its clinical management.
doi:10.1038/ng.2521
PMCID: PMC3793390  PMID: 23291588
10.  HCV RNA Levels in a Multi-Ethnic Cohort of Injection Drug Users: Human Genetic, Viral and Demographic Associations 
Hepatology (Baltimore, Md.)  2012;56(1):86-94.
In patients with chronic hepatitis C, the hepatitis C virus (HCV) RNA level is an important predictor of treatment response. To explore the relationship of HCV RNA with viral and demographic factors, as well as IL28B genotype, we examined viral levels in an ethnically diverse group of injection drug users (IDUs). Between 1998 and 2000, the Urban Health Study (UHS) recruited IDUs from street settings in San Francisco Bay area neighborhoods. Participants who were positive by HCV EIA were tested for HCV viremia by a bDNA assay. HCV genotype was determined by sequencing the HCV NS5B region. For a subset of participants, IL28B rs12979860 genotype was determined by Taqman. Among 1701 participants with HCV viremia, median age was 46 years and median duration of injection drug use was 26 years; 56.0% were African American and 34.0% were of European ancestry (non-Hispanic). HIV-1 prevalence was 13.9%. The overall median HCV RNA level was 6.45 log10 copies/ml. In unadjusted analyses, higher levels were found with older age, male gender, African American ancestry, HBV infection, HIV-1 infection and IL28B rs12979860-CC genotype; compared to participants infected with HCV genotype 1, HCV RNA was lower in participants with genotype 3 or genotype 4. In an adjusted analysis, age, gender, racial ancestry, HIV-1 infection, HCV genotype and IL28B rs12979860 genotype were all independently associated with HCV RNA. Conclusion: The level of HCV viremia is influenced by a large number of demographic, viral and human genetic factors.
doi:10.1002/hep.25652
PMCID: PMC3369001  PMID: 22331649
epidemiology; genetics; HCV; IL28B; viremia
11.  IL28B rs12979860 Genotype and Spontaneous Clearance of Hepatitis C Virus in a Multi-Ethnic Cohort of Injection Drug Users: Evidence for a Supra-Additive Association 
The Journal of Infectious Diseases  2011;204(12):1843-1847.
Among 1369 Urban Health Study participants, we evaluated genetic models for the association of IL28B genotype (rs12979860 and rs8099917) with hepatitis C virus (HCV) clearance. For rs12979860, adjusted odds ratios for spontaneous HCV clearance were as follows: IL28B-CC, 3.88 (P < .001); IL28B-CT, 1.48 (P = .08). On the basis of Akaike information criteria values and χ2 tests, a supra-additive (quadratic) model fit these data best. Models based on rs8099917 provided poorer fit. Evidence that a supra-additive rs12979860-based model best fits the association of IL28B-genotype with HCV clearance may improve clinical prediction models and foster a better understanding of functional mechanisms underlying this association.
doi:10.1093/infdis/jir647
PMCID: PMC3209810  PMID: 22013224
12.  A Functional Polymorphism in the Epidermal Growth Factor Gene is Associated with Risk for Hepatocellular Carcinoma 
Gastroenterology  2011;141(1):141-149.
Background & Aims
A single nucleotide polymorphism 61*G (rs4444903) in the Epidermal Growth Factor (EGF) gene has been associated, in 2 case-control studies, with hepatocellular carcinoma (HCC). We tested associations between demographic, clinical, and genetic data and development of HCC, and developed a simple predictive model in a cohort of patients with chronic hepatitis C and advanced fibrosis.
Methods
Black and white subjects from the HALT-C trial (n=816) were followed prospectively for development of a definite or presumed case of HCC for a median time period of 6.1 years. We used the Cox proportional hazards regression model to determine the hazard ratio for risk of HCC and to develop prediction models.
Results
Subjects with EGF genotype G/G had a higher adjusted risk for HCC than those with genotype A/A (hazard ratio, 2.10; 95% confidence interval, 1.05–4.23; P=0.03). After adjusting for EGF genotype, blacks had no increased risk of HCC risk, compared with whites. Higher serum levels of EGF were observed among subjects with at least one G allele (P=0.08); the subset of subjects with EGF G/G genotype and above-median serum levels of EGF had the highest risk of HCC. We developed a simple prediction model that included the EGF genotype to identify patients at low, intermediate, and high risk for HCC; 6-year cumulative HCC incidences were 2.3%, 10.4%, and 26%, respectively.
Conclusions
We associated the EGF genotype G/G with increased risk for HCC; differences in its frequency among black and white subjects might account for differences in HCC incidence between these groups. We developed a model that incorporates EGF genotype and demographic and clinical variables to identify patients at low, intermediate, and high risk for HCC.
doi:10.1053/j.gastro.2011.03.045
PMCID: PMC3129453  PMID: 21440548
liver disease; cancer; tumor; prognosis; HCV
13.  Genetic Variation in CLDN1 and Susceptibility to Hepatitis C Virus Infection 
Journal of viral hepatitis  2009;17(3):192-200.
Claudin-1 is a recently discovered co-receptor for hepatitis C virus (HCV) that is required for late-stage binding of the virus. Because variants in the gene that encodes claudin-1 (CLDN1) could play a role in HCV infection, we conducted a ‘whole gene association study’ among injection drug users (IDUs) to examine whether CLDN1 genetic variants were associated with the risk of HCV infection or with viral clearance. In a cross sectional study, we examined genotype results for 50 single nucleotide polymorphisms (SNPs) across the CLDN1 gene region, comparing genotypes among participants with chronic HCV (n=658) to those in IDUs who had cleared HCV (n=199) or remained HCV-uninfected (n=68). Analyses were controlled for racial ancestry (African American or European American) by stratification and logistic regression modeling. We found that participants who remained uninfected more often carried CLDN1 promoter region SNPs -15312C [odds ratio (OR), 1.72; 95% confidence interval (CI) 1.00-2.94; p=0.048], -7153A (OR, 2.13; 95% CI, 1.25-3.62; p=0.006) and -5414C (OR, 1.78; 95% CI, 1.06-3.00; p=0.03). HCV-uninfected participants less often carried CLDN1 IVS1-2983C (OR, 0.55; 95% CI, 0.31-0.97; p=0.04), which lies in intron 1. CLDN1 -15312C, -7153A and -5414C formed a haplotype in both the African American and European American participants and a haplotype analysis supported the association of CLDN1 -7153A in the HCV-uninfected participants. The analyses of HCV clearance revealed no associations with any SNP. These results indicate that genetic variants in regulatory regions of CLDN1 may alter susceptibility to HCV infection.
doi:10.1111/j.1365-2893.2009.01166.x
PMCID: PMC2921226  PMID: 19674288
claudin-1; epidemiology; genetic; susceptibility; viral receptor
14.  Population Genetics and Comparative Genetics of CLDN1, a Gene Involved in Hepatitis C Virus Entry 
Human Heredity  2008;67(3):206-216.
The claudin-1 gene (CLDN1) is a member of a family of genes that encodes proteins found in tight junctions and it has recently been implicated as one of several receptors for late stage binding of hepatitis C virus (HCV). Exploration of the population genetics of this gene could be informative, especially in the investigation of a possible genetic contribution to HCV infection. Comparison to a highly similar gene, claudin-7 (CLDN7) could provide insight into the recent molecular evolution of CLDN1. Mean interspecies conservation score was 0.11 (SD 0.28) for CLDN1 and 0.31 (SD 0.43) for CLDN7. Re-sequence analysis was performed across all exons and evolutionarily conserved regions in CLDN1 (13 kb in total) and CLDN7 (2 kb in total) in 204 chromosomes drawn from the SNP500Cancer resource of four self-described ethnic groups in the US. For CLDN1, 133 SNPs were identified as well as 8 indels and an AC repeat length polymorphism. For CLDN7, 5 SNPs were identified. Assessment of nucleotide diversity (including Fst, θ and π statistics) did not show evidence for recent positive or negative selection in either gene. The pattern of linkage disequilibrium was determined for each group and there is substantial difference for common SNPS (>5%) between populations as well as genes, further supporting the absence of signatures of recent selection.
doi:10.1159/000181159
PMCID: PMC2868922  PMID: 19077439
Hepatitis C virus; Population genetics; Evolution; Selection; Conservation; Tight junctions; Viral receptor
15.  DNA polymorphisms and response to treatment in patients with chronic hepatitis C: Results from the HALT-C trial 
Journal of hepatology  2008;49(4):548-556.
Background/Aim
Certain host genetic polymorphisms reportedly affect the likelihood of a sustained virological response (SVR) to interferon treatment in subjects infected with hepatitis C virus (HCV). As part of the HALT-C trial we evaluated genetic associations among patients infected with HCV genotype 1 who had failed previous interferon treatment.
Methods
SVR was determined 24 weeks after completing treatment with pegylated interferon alfa-2a and ribavirin. Eight single nucleotide polymorphisms (SNPs) were selected on the basis of previously reported associations with treatment response. Genotypes were assessed by polymerase chain reaction-based assays. The percentage of patients who achieved SVR was determined for each genotype and for an IL-10 promoter diplotype.
Results
Among 637 non-Hispanic Caucasian patients there were no significant associations between genotype for any individual SNP (IL10 -1082, IL10 -592, TNF -308, TNF -238, TGFB1 codon 25, CCL2 -2518, EPHX1 codon 113 and AGT -6) and SVR, but SVR was more common among the patients who were homozygous for the ACC IL-10 promoter diplotype (adjusted odds ratio, 3.24; 95% confidence interval, 1.33–7.78; p=0.001).
Conclusions
Among non-Hispanic Caucasian patients treated with peginterferon and ribavirin after failing previous treatment with interferon, homozygosity for the ACC IL-10 promoter diplotype was associated with SVR.
doi:10.1016/j.jhep.2008.05.011
PMCID: PMC3903339  PMID: 18619701
hepatitis C; chronic/genetics; polymorphism; genetic; interferon-alpha/therapeutic use; gene frequency
16.  Quality Assessment of Microarray Data in a Multicenter Study 
Issues implicit in a multicenter microarray study are protocol standardization and monitoring center adherence to established protocols. This study explored the effects of submitting center and sample preservation method on the quality of isolated RNA. In addition, the effects of sample preservation method and laboratory on microarray quality were also examined. Herein we evaluated the contribution of specific technical factors [center, laboratory, and preservation method (frozen/RNAlater)] on quality of isolated RNA, cRNA synthesis products, and reproducibility of gene expression microarray data for independent biologic samples collected in a multicenter microarray study. The Kruskal-Wallis test was used to test for differences owing to submitting center on isolated RNA quality. Mixed effects analysis of variance was used in assessing the impact of laboratory and preservation method on gene expression values for the 12 samples hybridized at 2 independent laboratories (24 GeneChips). One center was found to be in violation of the tissue handling protocol. No significant effect was noted owing to preservation method, which ensured that our tissue handling protocols are working properly. There was a significant laboratory effect with respect to cRNA yield, though this effect did not impact sample quality. We conclude that use of consistent protocols for sample collection, RNA extraction, cDNA/cRNA synthesis, labeling, hybridization, platform, image acquisition, normalization, and expression summaries can yield consistent expression values. Moreover, evaluation of sample quality at various steps in the data acquisition process is an important component of a multicenter study to ensure all participating centers adhere to established protocols.
doi:10.1097/PDM.0b013e3181731e14
PMCID: PMC3738008  PMID: 19214110
microarray; multicenter study; gene expression; Affymetrix GeneChip; quality
18.  Hepatitis C Virus Infection, Linxian, China1 
Emerging Infectious Diseases  2005;11(1):17-21.
The prevalence of HCV infection was high among older citizens of Linxian, China, in 2000.
Bloodborne viruses may have spread in rural China during the past 25 years, but population-based prevalence estimates are lacking. We examined the frequency of hepatitis C virus (HCV) and HIV type 1 (HIV-1) among residents of Linxian, a rural community in Henan Province. In 2000, blood was collected from participants (>55 years of age) who had enrolled in a population-based nutritional intervention trial in 1985. We randomly selected 500 participants for HCV testing and 200 participants for HIV-1 testing. For HCV, 48 (9.6%) of 500 participants were positive by enzyme immunoassay and recombinant immunoblot assay (95% confidence interval [CI], 7.0%–12.2%), and prevalence was lowest in the most geographically isolated participants. Among the HCV-infected participants, 42 had a specimen available from1985, of which 16 (38.1%) were positive for HCV. For HIV-1, 0/200 participants were positive. We conclude that HCV is now a common infection among older adults in Linxian, China.
doi:10.3201/eid1101.031005
PMCID: PMC3294338  PMID: 15705317
AIDS; China; epidemiology; hepatitis B virus (HBV); hepatitis C virus (HCV); human immunodeficiency virus type 1 (HIV-1); liver cancer; prevalence; research
20.  Interferon-lambda and therapy for chronic hepatitis C virus infection 
Trends in immunology  2011;32(9):443-450.
Interferon (IFN)-α, a type-I IFN, is widely used to treat chronic hepatitis C virus (HCV) infection, but the broad expression of IFN-α receptors often leads to adverse reactions in many organs. Here, we examine IFN-λ, a type-III IFN, as a therapeutic alternative to IFN-α. Like IFN-α, IFN-λ also induces antiviral activity in hepatocytes, but may induce fewer adverse reactions because its receptor is largely restricted to cells of epithelial origin. We also discuss the recent discovery of single nucleotide polymorphisms (SNPs) near the human IFN-λ3 gene, IL28B, that correlate strongly with the ability to achieve a sustained virologic response (SVR) to therapy with pegylated IFN-α plus ribavirin in patients with chronic hepatitis C.
doi:10.1016/j.it.2011.07.002
PMCID: PMC3163738  PMID: 21820962
22.  HLA-B alleles associate consistently with HIV heterosexual transmission, viral load and progression to AIDS, but not susceptibility to infection 
AIDS (London, England)  2010;24(12):1835-1840.
Objective
HLA class I polymorphism is known to affect the rate of progression to AIDS after infection with HIV-1. Here we test the consistency of HLA-B allelic effects on progression to AIDS, heterosexual HIV transmission and ‘setpoint’ viral levels.
Methods
We used adjusted Cox proportional hazard models in previously published relative hazard (RH) values for the effect of HLA-B alleles on progression to AIDS (n=1089). The transmission study included 303 HIV-1-infected men with hemophilia and their 323 female sex partners (MHCS cohort). Among 259 HIV-1 seroconverters (MACS cohort), HIV RNA levels at ‘setpoint’ were determined in stored plasma samples by a reverse-transcription polymerase chain reaction assay. HLA-B genotyping was performed by sequence-specific-oligonucleotide-hybridization and DNA sequencing.
Results
Several HLA-B alleles showed consistent associations for AIDS risk, infectivity and ‘setpoint’ HIV RNA. HLA-B*35 was associated with more rapid progression to AIDS (RH 1.39; p = 0.008), greater infectivity (OR 3.14; p = 0.002), and higher HIV RNA (p = 0.01), whereas the presence of either B*27 or B*57 associated with slower progression to AIDS (B*27: RH 0.49, p < 0.001; B*57: RH 0.40, p <0.0001), less infectivity (OR 0.22 and 0.31, respectively, though not significant) and lower viral levels (p <0.0001). Importantly, HLA-B polymorphism in female partners was not associated with susceptibility to HIV-1 infection.
Conclusion
HLA-B polymorphisms that affect the risk of AIDS may also alter HIV-1 infectivity, probably through the common mechanism of viral control, but they do not appear to protect against infection in our cohort.
doi:10.1097/QAD.0b013e32833c3219
PMCID: PMC2902625  PMID: 20588164
HIV; AIDS; HLA; viral load; HIV transmission; AIDS progression; MHC diversity
23.  An IL28B Genotype-Based Clinical Prediction Model for Treatment of Chronic Hepatitis C 
PLoS ONE  2011;6(7):e20904.
Background
Genetic variation in IL28B and other factors are associated with sustained virological response (SVR) after pegylated-interferon/ribavirin treatment for chronic hepatitis C (CHC). Using data from the HALT-C Trial, we developed a model to predict a patient's probability of SVR based on IL28B genotype and clinical variables.
Methods
HALT-C enrolled patients with advanced CHC who had failed previous interferon-based treatment. Subjects were re-treated with pegylated-interferon/ribavirin during trial lead-in. We used step-wise logistic regression to calculate adjusted odds ratios (aOR) and create the predictive model. Leave-one-out cross-validation was used to predict a priori probabilities of SVR and determine area under the receiver operator characteristics curve (AUC).
Results
Among 646 HCV genotype 1-infected European American patients, 14.2% achieved SVR. IL28B rs12979860-CC genotype was the strongest predictor of SVR (aOR, 7.56; p<.0001); the model also included HCV RNA (log10 IU/ml), AST∶ALT ratio, Ishak fibrosis score and prior ribavirin treatment. For this model AUC was 78.5%, compared to 73.0% for a model restricted to the four clinical predictors and 60.0% for a model restricted to IL28B genotype (p<0.001). Subjects with a predicted probability of SVR <10% had an observed SVR rate of 3.8%; subjects with a predicted probability >10% (43.3% of subjects) had an SVR rate of 27.9% and accounted for 84.8% of subjects actually achieving SVR. To verify that consideration of both IL28B genotype and clinical variables is required for treatment decisions, we calculated AUC values from published data for the IDEAL Study.
Conclusion
A clinical prediction model based on IL28B genotype and clinical variables can yield useful individualized predictions of the probability of treatment success that could increase SVR rates and decrease the frequency of futile treatment among patients with CHC.
doi:10.1371/journal.pone.0020904
PMCID: PMC3132753  PMID: 21760886
24.  Splicing Diversity of the Human OCLN Gene and Its Biological Significance for Hepatitis C Virus Entry▿ †  
Journal of Virology  2010;84(14):6987-6994.
Persistent hepatitis C virus (HCV) infection is a primary etiological factor for the development of chronic liver disease, including cirrhosis and cancer. A recent study identified occludin (OCLN), an integral tight junction protein, as one of the key factors for HCV entry into cells. We explored the splicing diversity of OCLN in normal human liver and observed variable expression of alternative splice variants, including two known forms (WT-OCLN and OCLN-ex4del) and six novel forms (OCLN-ex7ext, OCLN-ex3pdel, OCLN-ex3del, OCLN-ex3-4del, OCLN-ex3p-9pdel, and OCLN-ex3p-7pdel). Recombinant protein isoforms WT-OCLN and OCLN-ex7ext, which retained the HCV-interacting MARVEL domain, were expressed on the cell membrane and were permissive for HCV infection in in vitro infectivity assays. All other forms lacked the MARVEL domain, were expressed in the cytoplasm, and were nonpermissive for HCV infection. Additionally, we observed variable expression of OCLN splicing forms across human tissues and cell lines. Our study suggests that the remarkable natural splicing diversity of OCLN might contribute to HCV tissue tropism and possibly modify the outcome of HCV infection in humans. Genetic factors crucial for regulation of OCLN expression and susceptibility to HCV infection remain to be elucidated.
doi:10.1128/JVI.00196-10
PMCID: PMC2898237  PMID: 20463075
25.  Variants in Interferon-α Pathway Genes and Response to Pegylated-Interferon-α2a plus Ribavirin for Treatment of Chronic HCV Infection in the HALT-C Trial 
Hepatology (Baltimore, Md.)  2009;49(6):1847-1858.
Combination treatment with pegylated-interferon-α and ribavirin, the current recommended therapy for chronic hepatitis C virus (HCV) infection, results in a sustained virological response (SVR) in only about half of patients. Because genes involved in the interferon-α pathway may affect anti-viral responses, we analyzed the relationship between variants in these genes and SVR among participants in the HALT-C trial. Patients had advanced chronic hepatitis C and had previously failed to respond to interferon-based treatment. Participants were treated with peginterferon-α2a and ribavirin during the trial. Subjects with undetectable HCV RNA at week 72 were considered to have had an SVR. Subjects with detectable HCV RNA at week 20 were considered non-responders. We used TaqMan assays to genotype 56 polymorphisms found in 13 genes in the interferon-α pathway. This analysis compares genotypes for participants with an SVR to non-responders. The primary analysis was restricted to European American participants because a priori statistical power was low among the small number (n=131) of African American patients. We used logistic regression to control the effect of other variables that are associated with treatment response. Among 581 European American patients, SVR was associated with IFNAR1 IVS1-22G (adjusted odds ratio [aOR], 0.57; p=0.02); IFNAR2 Ex2-33C (aOR, 2.09; p=0.02); JAK1 IVS22+112T (aOR, 1.66; p=0.04); and ADAR Ex9+14A (aOR, 1.67; p=0.03). For the TYK2 -2256A promoter region variant a borderline association was present among European American participants (OR, 1.51; p=0.05) and a strong relationship among African American patients; all 10 with SVR who were genotyped for TYK2-2256 carried the A variant compared to 68/120 (57%) non-responders (p=0.006). In conclusion, genetic polymorphisms in the interferon-α pathway may affect responses to antiviral therapy of chronic hepatitis C.
doi:10.1002/hep.22877
PMCID: PMC2692559  PMID: 19434718
epidemiology; hepatitis C/genetics; chronic; interferon-alpha/therapeutic use; gene frequency; pharmacogenetics; polymorphism; genetic

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