CTL escape mutations of core protein are more frequent in strains of HBeAg negative patients with low levels of HBV DNA

Sendi, Hossein; Mehrab-Mohseni, Marjan; Shahraz, Saeid; Nordér, Helené; Alavian, Seyed Moayed; Noorinayer, Babak; Zali, Mohammad Reza; Pumpens, Paul; Bonkovsky, Herbert L.; Magnius, Lars O.

doi:10.1016/j.jcv.2009.08.002

Cited by 25 publications

(33 citation statements)

References 25 publications

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“…Interestingly, this mutant epitope had been suggested to act as T-cell receptor antagonist leading to inhibition of the CTL response to the wild type CTL epitope, 31 and the S21 substitution was considered to be a CTL escape mutation. 32 However, of our 3 FHB patients whose HLA-A types were known, 2 patients with S21 substitution did not have HLA-A2 (data not shown). Therefore the pathogenesis might not be necessarily due to the immune escape.…”

Section: Discussionmentioning

confidence: 73%

Association between S21 substitution in the core protein of hepatitis B virus and fulminant hepatitis

Inoue

Ueno

Kawamura

et al. 2012

Journal of Clinical Virology

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Section: Discussionmentioning

confidence: 73%

Association between S21 substitution in the core protein of hepatitis B virus and fulminant hepatitis

Inoue

Ueno

Kawamura

et al. 2012

Journal of Clinical Virology

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“…Similarly, CTL epitopes at positions 88 to 96 and 141 to 151 are restricted by HLA-A11 and HLA-Aw68, respectively (9). Substitution L60V (SZ5) was previously described as related to low-level production of HBV virions (16). Mutations of I97(L/T) and P130T were identified in 60% (3/5) and 40% (2/5) OBI strains.…”

Section: Discussionmentioning

confidence: 93%

“…The mutations of core protein in HBV infection have been reported associated with not only severe liver disease but also low secretion of HBV virions and immune escape epitopes at Th and CTL levels (3,11,16). Mutations of OBI core proteins (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Mutations of OBI core proteins (Fig. 1) showing amino acid substitutions in the CTL epitope clusters 18 to 27, 88 to 96, and 141 to 151 might constitute escape epitopes and contribute to the persistence of HBV infection despite reducing viral fitness (16). The CTL epitope at positions 18 to 27 is restricted by HLA-A2, but the potential impact of substitutions at position 21 and 26 is not known (2).…”

Section: Discussionmentioning

confidence: 99%

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Characterization of Occult Hepatitis B Virus Infection from Blood Donors in China

Zheng

Wang

et al. 2011

J Clin Microbiol

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Prevalence and characteristics of occult hepatitis B virus (HBV) infection (OBI) of genotypes B and C prevalent inChina have not been extensively explored. Characterization of OBI strains obtained from Chinese blood donors was based on clinical and serological analyses, follow-up testing, and sequence analyses. Twentyeight samples from 165,371 HBV surface antigen (HBsAg)-negative plasmas were confirmed HBsAg negative and DNA positive(HBsAg ؊ /DNA ؉ ), of which 22 were classified as OBIs and 6 as window period infections. The OBI incidence was 1:7,517 in blood donors, whose ages ranged between 20 and 45 years (median, 28 years). OBI donors had normal alanine aminotransferase (ALT) levels and low viral loads ranging between unquantifiable amounts and 178 IU/ml (median, 14 IU/ml). Sequences from 21 basic core promoter/precore (BCP/PC) regions, five whole genomes, and two additional pre-S/S regions from OBI strains were compared to genotypes B and C HBsAg ؉ reference strains. Eighty-six percent (6/7) of OBI strains were genotype C. Deletions, insertions, stop codons, and substitutions were detected in 15/21 (71%) core regulatory elements of OBI strains. Critical mutations were found in the core proteins of 5/5 OBI strains in parallel with random substitutions in pre-S/S proteins from 6/7 (86%) OBI strains. Critical mutations in core regulatory elements and core proteins might affect OBI genotype B and C strain replication. That there were few S protein substitutions suggests a minor role of the host immune defenses in OBI occurrence.Hepatitis B virus (HBV) infection is a major threat to human health worldwide, especially to people living in developing countries. The number of HBV carriers with detectable surface antigen (HBsAg) is estimated to be over 300 million globally, while there are around 100 million HBVinfected individuals in mainland China (12). HBV serological testing is widely used in controlling the risk of HBV transmission among people who donate blood or have health examinations in China. However, some studies recently showed HBV DNA at low levels detected in HBsAgnegative individuals, some of whom transmitted HBV infections to recipients of blood transfusions (10). Occult hepatitis B virus infection (OBI) is defined as the detection of HBV DNA in the serum or liver tissue of patients who test negative for HBsAg (15). Currently, testing for HBsAg is performed for screening of HBV infection in blood donors in China, but nucleic acid testing (NAT) is not used.A characterization of OBI strains of genotypes A1, A2, D, and E in comparison with wild-type HBV in samples obtained from European and African blood donors was recently published. The mechanisms for generating OBI strains were mainly related to either imperfect immune control or to genetic viral defects and appeared largely genotype dependent (1, 4). However, analysis of OBI strains of genotypes B and C prevalent in Southeast Asia and China has not been extensively explored, particularly in terms of molecular characterization (14,20).This study prov...

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“…This protein, being secreted, was proposed to cause a "split tolerance," which consists of a Th2-type immune response, with promotion of antibody production limiting the Th1 response. On the other hand, a CD8 ϩ T-cell response against core-derived epitopes has been shown (7,22,41,42,52,55). One can thus assume that in the HBeAg region, selection against the CD8 ϩ T cell epitope is taking place.…”

Section: Resultsmentioning

confidence: 99%

Immune-Induced Evolutionary Selection Focused on a Single Reading Frame in Overlapping Hepatitis B Virus Proteins

Maman

Blancher

Benichou

et al. 2011

J Virol

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Viruses employ various means to evade immune detection. Reduction of CD8؉ T cell epitopes is one of the common strategies used for this purpose. Hepatitis B virus (HBV), a member of the Hepadnaviridae family, has four open reading frames, with about 50% overlap between the genes they encode. We computed the CD8 ؉ T cell epitope density within HBV proteins and the mutations within the epitopes. Our results suggest that HBV accumulates escape mutations that reduce the number of epitopes. These mutations are not equally distributed among genes and reading frames. While the highly expressed core and X proteins are selected to have low epitope density, polymerase, which is expressed at low levels, does not undergo the same selection. In overlapping regions, mutations in one protein-coding sequence also affect the other protein-coding sequence. We show that mutations lead to the removal of epitopes in X and surface proteins even at the expense of the addition of epitopes in polymerase. The total escape mutation rate for overlapping regions is lower than that for nonoverlapping regions. The lower epitope replacement rate for overlapping regions slows the evolutionary escape rate of these regions but leads to the accumulation of mutations more robust in the transfer between hosts, such as mutations preventing proteasomal cleavage into epitopes.

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CTL escape mutations of core protein are more frequent in strains of HBeAg negative patients with low levels of HBV DNA

Abstract: Background-Recent studies have suggested that Cytotoxic T lymphocytes (CTL) play a key role in eliminating hepatitis B virus (HBV).

Cited by 25 publications

References 25 publications

Association between S21 substitution in the core protein of hepatitis B virus and fulminant hepatitis

Association between S21 substitution in the core protein of hepatitis B virus and fulminant hepatitis

Characterization of Occult Hepatitis B Virus Infection from Blood Donors in China

Immune-Induced Evolutionary Selection Focused on a Single Reading Frame in Overlapping Hepatitis B Virus Proteins

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