Hepatitis Monthly
Volume:19 Issue: 8, Aug 2019

Immune escape mutation is a major reason for vaccination failure in vertical transmission of hepatitis B virus (HBV).

The aim of the current study was to explore the characteristics of HBV S region gene in vertical transmission and the influence of mutations on vaccination failure in HBV S region gene.

A total of nine mother-child pairs with chronic HBV were recruited in this study, and all of the children received the vaccine. Next-generation sequencing (NGS) was used to investigate the sequences of HBV S gene from the mother and children.

The analysis of the sequencing data showed that all mother-child pairs are genotype B and genotype C mixed infection and the dominant genotype did not change in vertical transmission, and the consensus sequences of mothers and children were highly similar. Furthermore, the diversity of most amino acid sites had a small difference between mothers and children, and the mutations shared by mothers and children made up a high proportion of children’s mutations; the rate was 83.13%  8.45%. Also, the research found many mutations that could cause immune escape in major hydrophilic region. Especially in “a” determinant, sC137S or sC139Y, which had an important influence on the structure of “a” determinant, were observed in all mother-child pairs.

All the above results indicated that HBV S gene was highly conserved in vertical transmission, and these immune escape mutations that pre-exist in mothers were transmitted to children and resulted in vaccination failure.

Hepatitis C virus (HCV) is a major public health problem in the Middle East and North Africa (MENA) region with an estimate of over 15 million chronically infected patients. However, molecular characterization of circulating genotypes in the MENA region remains elusive. Here, weperformed a comparative phylogenomic analysis of so-far available E1 gene sequences (937), originating from eight countries in the MENA region. All HCV E1 protein sequences present in NCBI from the MENA region were retrieved and cataloged per year and country of origin. Phylogenetic analysis revealed a maximum diversity of genotypes and subtypes in South Arabia [G-1 (1a, 1b, 1g), G-2 (2a, 2c), G-3 (3a) and G-4 (4a, 4d, 4n, 4o, 4r, 4s)] followed by Egypt [G-1 (1b, 1g) and G-4 (4a, 4l, 4n, 4m, 4u)], Iran [G-1 (1b) and G-3 (3a) G-6 (6a)], Tunisia [G-1 (1b) and G-2 (2a, 2b, 2c)], Algeria [G-1 (1i), 4(4f), Pakistan [G-1 (1a), G-3(3a, 3b)], Afghanistan [G-1 (1a), GT-3 (3a)], and 5(5a), and Yemen [G-4 (4r)]. The calculated evolution rate of retrieved sequences was 1.60110-3 substitutions/site/year and the mean nucleotide diversity rate was 0.2684 (P < 0.001). The ratio of synonymous to non-synonymous (mean dN/dS) substitutions was higher in genotypes 2 and 4 compared to the genotypes 1 and 3. A higher degree of nucleotide identity in E1 gene was found between subtypes 1a and 1b, between 2c and 2g, and between 4a, 4d, and 4o. Comparative residue analysis of E1 protein epitope sequences of previously reported H111, A4, and A6 monoclonal antibodies showed relatively poor and genotype-specific conservancy. Perhaps, none of the reported epitope sequences had immunogenicity score higher than 0.4 (A minimum threshold for vaccine sequence prediction). Furthermore, these epitope sequences were heavily glycosylated at amino acid 196, 209, and 234 sites in all GTs. In conclusion, a high genetic variability in E1 protein coupled with increased glycosylation may deduce heterogeneity and subsequent escape from vaccine-generated immune response, thereby ascertaining necessary interventions for disease management and control.

Context:

Chronic viral hepatitis (CVH), a world health problem, is the leading cause of hepatocellular carcinoma (HCC). Host immunity plays a critical role in viral clearance, development and progression of the disease. Mucosal-associated invariant T (MAIT) cells represent an abundant form of innate T cells, which plays an essential role in infectious diseases with releasing cytokine, lysing target cells, and shaping adaptive immunity.

Although numerous studies showed the immune profiles of MAIT cells in CVH, the results are inconsistent. Thus, we performed a meta-analysis to analyze the immune profiles of MAIT cells in CVH. Evidence Acquisition: PubMed, Embase, the Cochrane Library, Google Scholar,  ScienceDirect, Web of Science, and the China National Knowledge Infrastructure (CNKI) were searched and 10 studies were included. Data from each study were compared using the standardized mean difference (SMD) with 95% confidence interval (CI). The quality assessment of studies and publication bias were evaluated by Newcastle-Ottawa scale and Begg’s and Egger’s tests, respectively, and a P value of < 0.05 was considered statistically significant.

Meta-analysis of the enrolled studies showed that the frequency of MAIT cells was significantly lower in patients with CVH as compared to healthy controls (SMD = -0.90, 95% CI: -1.32 to -0.48, P < 0.0001). In addition, MAIT cells displayed an activated and exhausted phenotype (CD38: SMD = 0.75, 95% CI: 0.38 to 1.13, P < 0.0001; HLA-DR: SMD = 1.42, 95% CI: 1.02 to 1.83, P < 0.00001; PD-1:SMD = 0.69, 95% CI: 0.13 to 1.26, P = 0.02; CTLA-4: SMD = 0.97, 95% CI: 0.40 to 1.54, P = 0.0008) but not impaired function during CVH (IFN- SMD = 0.04, 95% CI: -0.28 to 0.37, P = 0.79; TNF-: SMD = -0.80, 95% CI: -1.77 to 0.16, P = 0.10; Granzyme B: SMD = -0.14, 95% CI:-0.58 to 0.29, P = 0.53; Perforin: SMD = -0.27, 95% CI: -0.87 to 0.33, P = 0.38).

In CVH patients, MAIT cells are significantly depleted in the peripheral bloodstream and displayed an activated and exhausted phenotype; however, the reduction of peripheral blood MAIT cells accompanied by activated and exhausted phenotypes may not impair the cytolytic function and cytokine production of these cells.

The enzyme ALAD (delta-aminolevulinic acid dehydratase), encoded by the ALAD gene, catalyzes the synthesis of porphobilinogen. The 177G>C (rs1800435) polymorphism participates in the hereditary deficiency of porphobilinogen synthase to cause acute lead poisoning.

The current study aimed at investigating the allelic frequency of the enzyme ALAD in patients with non-alcoholic fatty liver disease (NAFLD) compared to the control group.

The fatty liver index (FLI) algorithm was used to diagnose NAFLD in participants of a prospective cohort of the Digestive Diseases Research Institute (DDRI). The ALAD genotypes, ALAD1 and ALAD2, were identified in 100 patients with NAFLD and 200 healthy controls using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP).

The C-allele of ALAD rs1800435 frequency was 5.5% in the group of patients with NAFLD compared to 3.3% in the control group, without significant differences (P = 0.37); however, alleles were in the Hardy-Weinberg equilibrium (P > 0.05). Serum ALT level was considerably higher in the ALAD2 carriers group than in the ones not carrying ALAD2 (29.413.9 vs. 19.410.1, P = 0.041). Nonetheless, each C-allele increased the serum ALT level by 1.24 IU/L (95% confidence interval: 0.22 - 2.67; P = 0.04).

The 177G>C (rs1800435) polymorphism in patients with NAFLD was similar to that of the normal population; however, it can be considered as a risk factor for serum ALT level increase.