Most people with hepatitis C virus (HCV) develop chronic infection with persistent viremia. Resolution of infection is associated with antiviral cellular immune responses of T helper 1 (Th1) type. Interleukin-12 (IL-12) is a key cytokine in the generation of Th1 responses, and functionally relevant polymorphisms of the IL12B gene and its promoter have been described recently. We sought an association between three IL12B polymorphisms and outcome of HCV infection in 195 HCV antibody-positive patients; 123 were chronically infected with detectable HCV RNA, and 72 had spontaneously resolved infection testing repeatedly negative for HCV RNA. Genotyping was performed for a single nucleotide polymorphism (SNP) in the 3'-UTR (1188A/C) of the IL12B gene and for 4-bp insertion/deletion polymorphisms in the IL12B promoter region and in the intron 4 region of the IL12B gene. We found chronically infected patients were significantly more likely than those with resolved HCV infection to be homozygous for the 3'-UTR A allele (66% vs. 50%; chi-square = 4.12, p = 0.04 with Yates correction), which has been associated with lower IL-12 production. No other significant association was found. Our findings support the concept that an individual's genetically determined ability to produce IL-12 is another factor that can influence the outcome of HCV infection.

SummaryCellular immunity with interferon gamma production could have a role in protection from hepatitis C virus (HCV). Interleukin (IL)-12 is a key cytokine in promoting such anti-viral T helper 1 (Th1) responses. We hypothesized that a genetic background able to promote cellular responses may be associated with apparent protection from infection and have investigated the distribution of the functional 1188A/C polymorphism of IL-12B in HCV exposed but uninfected cases. The frequency of the high IL-12-producing C allele was determined by restriction enzyme genotyping in 76 exposeduninfected individuals and 105 healthy controls. Overall, the C allele was found in 27·6% of exposed-uninfected cases compared with 16·7% of healthy controls [c 2 = 6·3, P = 0·02, odds ratio (OR) = 1·9, 95% confidence interval (CI) = 1·1-3·2]. CC genotype was found in 10·5% of exposed-uninfected cases compared with 0·9% controls (c 2 = 9·3, P = 0·01, OR = 12, 95% CI = 1·5-100). Individuals at high risk of HCV infection yet who remain uninfected may be resistant in some way to infection. In our cohort of exposed-uninfected cases a genetic background of enhanced IL-12 production was associated with apparent resistance to HCV infection. This lends support to a central role for cellular immune responses in protecting from infection.

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Hepatitis C virus (HCV) is a major cause of chronic hepatitis, cirrhosis, and liver cancer occurring in up to 3% of the world's population. Parenteral exposure to HCV is the major mode of transmission of infection. Once established, infection will persist in up to 85% of individuals with only a minority of patients clearing viremia. Egypt has possibly the highest HCV prevalence in the world where 10-20% of the general population are infected with HCV. Endemic HCV appears to be concentrated in the tropics and sub-tropics where there are higher biting rates from insects. The question as to whether a bridge vector transmission is possible, via arthropods, both between humans and/or from an animal reservoir to humans is explored. Mechanical transmission, as opposed to biological transmission, is considered. Mechanical transmission can be an efficient way of transmitting an infection, as effective as biological transmission. Probability of transmission can increase as to the immediate circumstances and conditions at the time. Several factors may enhance mechanical transmission, including high levels of microbes in the vector, frequent biting, the close proximity, and contact between vectors and recipients as well as high density of insects. HCV has been isolated from bodies or heads of mosquitoes collected from the houses of HCV-infected individuals. The possibility of enzootic cycles of HCV tangential transmission via bridging vectors, such as, arthropods needs to be further investigated and possible animal reservoirs, including domestic rural epizootic cycles for HCV infection, requires further research with particular initial emphasis on equine infections. J. Med. Virol. 89:187-194, 2017. © 2016 Wiley Periodicals, Inc.

Several cell surface molecules have hepatitis C virus (HCV) binding properties and may serve as receptors facilitating viral entry into cells. The large extracellular loop (LEL) of CD81 has been shown to bind the HCV envelope protein E2 with several critical residues for the CD81-HCV-E2 interaction. It was hypothesised that variation in the CD81 LEL sequence may modify susceptibility to HCV infection. HCV RNA negative patients with spontaneous viral clearance (RNA -ve); HCV RNA positive cases, who are affected chronically (RNA +ve); and patients at high risk of HCV infection, exposed but uninfected patients (EU) were studied. Genomic DNA was extracted from whole blood samples and four exons of the CD81 LEL gene were amplified by PCR and sequenced. The cDNA derived from CD81 (≈700 bp) was sequenced following RNA extraction from peripheral blood mononuclear cells. Patients, who are RNA positive, RNA negative, and exposed uninfected were sequenced for four DNA sections (A, B, C, and D). Sixty-two (43M:19F) patients, from all the patient cohorts, were sequenced and compared for the C section alone (which encompasses the important binding region of the molecule for envelope protein) including 21 (14M:7F) HCV RNA negative, 15 (10M:5F) HCV RNA positive and 26 (20M:6F) exposed uninfected and no sequence differences were observed. The entire CD81 sequence from cDNA was obtained in 23 cases-11 RNA -ve, 5 RNA +ve and 7 EU. In 7 of the 23 cases, the nucleotides were confirmed with the genomic sequence (4 RNA -ve and 3 EU cases). No sequence variation was found in any of the patients studied by either method, including gene sections encoding the residues most important for CD81-HCV E2 binding. The LEL of CD81 is a molecule that is highly conserved. No differences in nucleotide sequence influencing susceptibility to, or outcome of HCV infection or evidence of methylation of the gene were found.