The Antiviral Efficacy of HIV-Specific CD8+ T-Cells to a Conserved Epitope Is Heavily Dependent on the Infecting HIV-1 Isolate

A major challenge to developing a successful HIV vaccine is the vast diversity of viral sequences, yet it is generally assumed that an epitope conserved between different strains will be recognised by responding T-cells. We examined whether an invariant HLA-B8 restricted Nef90–97 epitope FL8 shared between five high titre viruses and eight recombinant vaccinia viruses expressing Nef from different viral isolates (clades A–H) could activate antiviral activity in FL8-specific cytotoxic T-lymphocytes (CTL). Surprisingly, despite epitope conservation, we found that CTL antiviral efficacy is dependent on the infecting viral isolate. Only 23% of Nef proteins, expressed by HIV-1 isolates or as recombinant vaccinia-Nef, were optimally recognised by CTL. Recognition of the HIV-1 isolates by CTL was independent of clade-grouping but correlated with virus-specific polymorphisms in the epitope flanking region, which altered immunoproteasomal cleavage resulting in enhanced or impaired epitope generation. The finding that the majority of virus isolates failed to present this conserved epitope highlights the importance of viral variance in CTL epitope flanking regions on the efficiency of antigen processing, which has been considerably underestimated previously. This has important implications for future vaccine design strategies since efficient presentation of conserved viral epitopes is necessary to promote enhanced anti-viral immune responses

A 2018 Horizon Scan of Emerging Issues for Global Conservation and Biological Diversity.

This is our ninth annual horizon scan to identify emerging issues that we believe could affect global biological diversity, natural capital and ecosystem services, and conservation efforts. Our diverse and international team, with expertise in horizon scanning, science communication, as well as conservation science, practice, and policy, reviewed 117 potential issues. We identified the 15 that may have the greatest positive or negative effects but are not yet well recognised by the global conservation community. Themes among these topics include new mechanisms driving the emergence and geographic expansion of diseases, innovative biotechnologies, reassessments of global change, and the development of strategic infrastructure to facilitate global economic priorities

Germline bias dictates cross-serotype reactivity in a common dengue-virus-specific CD8(+) T cell response.

Adaptive immune responses protect against infection with dengue virus (DENV), yet cross-reactivity with distinct serotypes can precipitate life-threatening clinical disease. We found that clonotypes expressing the T cell antigen receptor (TCR) β-chain variable region 11 (TRBV11-2) were 'preferentially' activated and mobilized within immunodominant human-leukocyte-antigen-(HLA)-A*11:01-restricted CD8(+) T cell populations specific for variants of the nonstructural protein epitope NS3133 that characterize the serotypes DENV1, DENV3 and DENV4. In contrast, the NS3133-DENV2-specific repertoire was largely devoid of such TCRs. Structural analysis of a representative TRBV11-2(+) TCR demonstrated that cross-serotype reactivity was governed by unique interplay between the variable antigenic determinant and germline-encoded residues in the second β-chain complementarity-determining region (CDR2β). Extensive mutagenesis studies of three distinct TRBV11-2(+) TCRs further confirmed that antigen recognition was dependent on key contacts between the serotype-defined peptide and discrete residues in the CDR2β loop. Collectively, these data reveal an innate-like mode of epitope recognition with potential implications for the outcome of sequential exposure to heterologous DENVs

Immunodominant CD8+ T cell responses to HIV-1 infection - 'The good and the bad'

Many lines of evidence indicate that CD8+ T cells are important in the control of HIV-1 infection and this has led to much vaccine research focused at eliciting virus specific CTL. However to date, the few large-scale trials of HIV-1 vaccines designed to elicit CD8+ T cells have produced disappointing results. This has highlighted our incomplete knowledge of the factors that determine if such cells are capable of viral control. The aim of this thesis is to further characterise qualitative aspects of HIV-1 specific CTL that are associated with both good and bad anti-viral activity.HIV-1 specific CTL responses were investigated in three ways. Firstly, by longitudinally analysing an immunodominant HLA-B*08 restricted CD8+ T cell response in a single rapid progression patient. Secondly, HLA-B*40 restricted CTL responses to HIV-1 where characterised within a Chinese slow progressor cohort. Lastly, factors that affect the processing and presentation of certain overlapping HIV-1 specific CD8+ T cell epitopes were examined.The results of these studies reveal that subtle variations in both host and viral proteins can have a substantial impact on virus specific CTL and in turn may impact on the outcome of disease. The generation of HIV-1 specific CD8+ T cells is a complex process affected by many variables including the viral sequence of epitope flanking regions as well as polymorphisms in the proteins involved in antigen processing and presentation. To add a further layer of complexity, it appears that HIV-1 virus specific CTL can modulate their functionality throughout the course of infection. Such factors should therefore be taken into account during HIV-1 vaccine design.</p

Immunodominant CD8+ T cell responses to HIV-1 infection : 'the good and the bad'

Many lines of evidence indicate that CD8+ T cells are important in the control of HIV-1 infection and this has led to much vaccine research focused at eliciting virus specific CTL. However to date, the few large-scale trials of HIV-1 vaccines designed to elicit CD8+ T cells have produced disappointing results. This has highlighted our incomplete knowledge of the factors that determine if such cells are capable of viral control. The aim of this thesis is to further characterise qualitative aspects of HIV-1 specific CTL that are associated with both good and bad anti-viral activity. HIV-1 specific CTL responses were investigated in three ways. Firstly, by longitudinally analysing an immunodominant HLA-B*08 restricted CD8+ T cell response in a single rapid progression patient. Secondly, HLA-B*40 restricted CTL responses to HIV-1 where characterised within a Chinese slow progressor cohort. Lastly, factors that affect the processing and presentation of certain overlapping HIV-1 specific CD8+ T cell epitopes were examined. The results of these studies reveal that subtle variations in both host and viral proteins can have a substantial impact on virus specific CTL and in turn may impact on the outcome of disease. The generation of HIV-1 specific CD8+ T cells is a complex process affected by many variables including the viral sequence of epitope flanking regions as well as polymorphisms in the proteins involved in antigen processing and presentation. To add a further layer of complexity, it appears that HIV-1 virus specific CTL can modulate their functionality throughout the course of infection. Such factors should therefore be taken into account during HIV-1 vaccine design.EThOS - Electronic Theses Online ServiceGBUnited Kingdo