Differential immunodominance hierarchy OF CD8+ T cell responses in HLA-B*27:05 AND B*27:02-mediated control of HIV-1 infection

The well-characterized association between HLA-B*27:05 and protection against HIV disease progression has been linked to immunodominant HLA-B*27:05-restricted CD8+ T-cell responses toward the conserved Gag KK10 (residues 263 to 272) and polymerase (Pol) KY9 (residues 901 to 909) epitopes. We studied the impact of the 3 amino acid differences between HLA-B*27:05 and the closely related HLA-B*27:02 on the HIV-specific CD8+ T-cell response hierarchy and on immune control of HIV. Genetic epidemiological data indicate that both HLA-B*27:02 and HLA-B*27:05 are associated with slower disease progression and lower viral loads. The effect of HLA-B*27:02 appeared to be consistently stronger than that of HLA-B*27:05. In contrast to HLA-B*27:05, the immunodominant HIV-specific HLA-B*27:02-restricted CD8+ T-cell response is to a Nef epitope (residues 142 to 150 [VW9]), with Pol KY9 subdominant and Gag KK10 further subdominant. This selection was driven by structural differences in the F pocket, mediated by a polymorphism between these two HLA alleles at position 81. Analysis of autologous virus sequences showed that in HLA-B*27:02-positive subjects, all three of these CD8+ T-cell responses impose selection pressure on the virus, whereas in HLA-B*27:05-positive subjects, there is no Nef VW9-mediated selection pressure. These studies demonstrate that HLA-B*27:02 mediates protection against HIV disease progression that is at least as strong as or stronger than that mediated by HLA-B*27:05. In combination with the protective Gag KK10 and Pol KY9 CD8+ T-cell responses that dominate HIV-specific CD8+ T-cell activity in HLA-B*27:05-positive subjects, a Nef VW9-specific response is additionally present and immunodominant in HLA-B*27:02-positive subjects, mediated through a polymorphism at residue 81 in the F pocket, that contributes to selection pressure against HIV

Constrained pattern of viral evolution in acute and early HCV infection limits viral plasticity

Cellular immune responses during acute Hepatitis C virus (HCV) and HIV infection are a known correlate of infection outcome. Viral adaptation to these responses via mutation(s) within CD8+ T-cell epitopes allows these viruses to subvert host immune control. This study examined HCV evolution in 21 HCV genotype 1-infected subjects to characterise the level of viral adaptation during acute and early HCV infection. Of the total mutations observed 25% were within described CD8+ T-cell epitopes or at viral adaptation sites. Most mutations were maintained into the chronic phase of HCV infection (75%). The lack of reversion of adaptations and high proportion of silent substitutions suggests that HCV has structural and functional limitations that constrain evolution. These results were compared to the pattern of viral evolution observed in 98 subjects during a similar phase in HIV infection from a previous study. In contrast to HCV, evolution during acute HIV infection is marked by high levels of amino acid change relative to silent substitutions, including a higher proportion of adaptations, likely reflecting strong and continued CD8+ T-cell pressure combined with greater plasticity of the virus. Understanding viral escape dynamics for these two viruses is important for effective T cell vaccine design

Fahrzeugwerbung und Verkehrssicherheit Problemstudie: Inhaltsanalyse und Folgerungen

TIB: RN 6741 (104) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman

Verkehrserziehung in der Sekundarstufe I Situationsanalyse und Folgerungen

TIB: RN 7380 (3) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman

Identification of novel hepatitis B virus (HBV) T-cell epitopes and escape mutations in Asian individuals with chronic HBV infection using a population based approach

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Co-localisation of hepatitis C virus drug-resistant mutations and immune-driven adaptations: Relevance to therapy outcome

Recent advances in molecular virology have led to the development of novel small anti-HCV drugs that target specific viral proteins integral to the HCV life cycle. Preliminary studies using these agents have revealed a number of drug-resistance mutations within the target HCV proteins. We, and others, have previously demonstrated the influence of the host’s immune response on viral diversity at both the individual and population level and identified sites within the HCV genome that are under immune pressure. In this study, the frequency of pre-existing drug resistance mutations within a drug-naïve population is determined and the potential for drug and immune selective pressures to intersect at sites along the HCV genome is explored. We obtained complete or partial sequence of the NS3/4A protease and NS5B polymerase from plasma samples from 264 genotype 1 and 147 genotype 3 HCV-infected individuals. High-resolution Human Leucocyte Antigen (HLA) typing was performed on DNA samples from individuals in this cohort. The baseline occurrence of drug resistance mutations can be observed at low frequencies in the drug naïve population, explaining why many observed drug resistance mutations occur rapidly after introduction of the drug. Furthermore, there are overlaps in areas of NS3/4A protease and NS5B polymerase that are likely to be under immune pressure and therapy selection. However, this overlap between the selective pressures is likely to be genotype specific as the differences at the amino acid level between the genotypes produces limited overlap in the sites along the viral genome that are under immune pressure. Drug and immune selection pressures may act synergistically or as opposing forces in HCV proteins that are targeted by the new anti-HCV drugs. Accordingly, an individual’s HCV immune escape and drug resistance profile are likely to be critical influences on the outcome with specific antiviral treatments

The broad assessment of HCV genotypes 1 and 3 antigenic targets reveals limited cross-reactivity with implications for vaccine design.

OBJECTIVE: Developing a vaccine that is cross-reactive between HCV genotypes requires data on T cell antigenic targets that extends beyond genotype-1. We characterised T cell immune responses against HCV genotype-3, the most common infecting genotype in the UK and Asia, and assessed within genotype and between genotype cross-reactivity. DESIGN: T cell targets were identified in 140 subjects with either acute, chronic or spontaneously resolved HCV genotype-3 infection using (1) overlapping peptides and (2) putative human leucocyte antigens (HLA)-class-I wild type and variant epitopes through the prior assessment of polymorphic HCV genomic sites associated with host HLA, in IFNγ-ELISpot assays. CD4+/CD8+ T cell subsets were defined and viral variability at T cell targets was determined through population analysis and viral sequencing. T cell cross-reactivity between genotype-1 and genotype-3 variants was assessed. RESULTS: In resolved genotype-3 infection, T cells preferentially targeted non-structural proteins at a high magnitude, whereas in chronic disease T cells were absent or skewed to target structural proteins. Additional responses to wild type but not variant HLA predicted peptides were defined. Major sequence viral variability was observed within genotype-3 and between genotypes 1 and 3 HCV at T cell targets in resolved infection and at dominant epitopes, with limited T cell cross-reactivity between viral variants. Overall 41 CD4/CD8+ genotype-3 T cell targets were identified with minimal overlap with those described for HCV genotype-1. CONCLUSIONS: HCV T cell specificity is distinct between genotypes with limited T cell cross-reactivity in resolved and chronic disease. Therefore, viral regions targeted in natural HCV infection may not serve as attractive targets for a vaccine that aims to protect against multiple HCV genotypes