HLA-DQA1 & DQB1 variants associated with hepatitis B virus-related chronic hepatitis, cirrhosis & hepatocellular carcinoma

Background & objectives: Clinical outcome after hepatitis B virus (HBV) exposure varies extremely from spontaneous clearance to chronic hepatitis B and often progresses to liver cirrhosis (LC) and hepatocellular carcinoma (HCC). Host genetic factor plays an important role in the regulation of immune response. This study was aimed to investigate whether HLA class II DQA1 and DQB1 gene polymorphism were associated with chronic hepatitis B infection and in the development of HBV-related LC and HCC. Methods: DQA1 and DQB1 allele polymorphism were studied in 187 patients with HBV-related liver diseases (which included 73 chronic hepatitis B, 84 LC and 30 HCC patients) and 109 controls who had spontaneously recovered from HBV infection using polymerase chain reaction amplification with sequence-specific primers. Results: Our data suggested that DQA1*0101/2/4 [odds ratio (OR)=2.78; Pc=0.003], DQA1*0103 (OR=2.64; Pc=0.0007) and DQB1*0302/3 (OR=2.15; Pc=0.01) were associated with the protection from chronic HBV infection, whereas DQB1*0402 (OR=0.25; Pc=0.001) showed susceptible effect on chronic HBV infection. DQB1*0601 (OR=3.73; Pc=0.006) conferred protective effect from developing LC; similarly, DQB1*0302/3 (OR=5.53; Pc=0.05) and DQB1*0402 (OR=0.00; Pc=0.001) conferred protective effect from developing HCC. However, DQA1*0601 and DQB1*0503 showed susceptible effect on chronic HBV infection; these associations were no longer significant after Bonferroni correction. Interpretation & conclusions: Our results revealed HLA-DQA1*0101/2/4 - DQA1*0103 - DQB1*0302/3 and DQB1*0601 as protective and DQB1*0402 as risk alleles. The study suggests that various subtypes of HLA-DQA1 and DQB1 are associated with both HBV clearance and development of chronic HBV infections

Lentivector cryptic splicing mediates increase in CD34+ clones expressing truncated HMGA2 in human X-linked severe combined immunodeficiency.

X-linked Severe Combined Immunodeficiency (SCID-X1) due to IL2RG mutations is potentially fatal in infancy where 'emergency' life-saving stem cell transplant may only achieve incomplete immune reconstitution following transplant. Salvage therapy SCID-X1 patients over 2 years old (NCT01306019) is a non-randomized, open-label, phase I/II clinical trial for administration of lentiviral-transduced autologous hematopoietic stem cells following busulfan (6 mg/kg total) conditioning. The primary and secondary objectives assess efficacy in restoring immunity and safety by vector insertion site analysis (VISA). In this ongoing study (19 patients treated), we report VISA in blood lineages from first eight treated patients with longer follow up found a > 60-fold increase in frequency of forward-orientated VIS within intron 3 of the High Mobility Group AT-hook 2 gene. All eight patients demonstrated emergence of dominant HMGA2 VIS clones in progenitor and myeloid lineages, but without disturbance of hematopoiesis. Our molecular analysis demonstrated a cryptic splice site within the chicken β-globin hypersensitivity 4 insulator element in the vector generating truncated mRNA transcripts from many transcriptionally active gene containing forward-oriented intronic vector insert. A two base-pair change at the splice site within the lentiviral vector eliminated splicing activity while retaining vector functional capability. This highlights the importance of functional analysis of lentivectors for cryptic splicing for preclinical safety assessment and a redesign of clinical vectors to improve safety