Dataset Information

Abacavir induced T cell reactivity from drug naive individuals shares features of allo-immune responses.

ABSTRACT: Abacavir hypersensitivity is a severe hypersensitivity reaction which occurs exclusively in carriers of the HLA-B*57?01 allele. In vitro culture of PBMC with abacavir results in the outgrowth of abacavir-reacting CD8+ T cells, which release IFN? and are cytotoxic. How this immune response is induced and what is recognized by these T cells is still a matter of debate. We analyzed the conditions required to develop an abacavir-dependent T cell response in vitro. The abacavir reactivity was independent of co-stimulatory signals, as neither DC maturation nor release of inflammatory cytokines were observed upon abacavir exposure. Abacavir induced T cells arose in the absence of professional APC and stemmed from naïve and memory compartments. These features are reminiscent of allo-reactivity. Screening for allo-reactivity revealed that about 5% of generated T cell clones (n?=?136) from three donors were allo-reactive exclusively to the related HLA-B*58?01. The addition of peptides which can bind to the HLA-B*57?01-abacavir complex and to HLA-B*58?01 during the induction phase increased the proportion of HLA-B*58?01 allo-reactive T cell clones from 5% to 42%. In conclusion, abacavir can alter the HLA-B*57?01-peptide complex in a way that mimics an allo-allele ('altered self-allele') and create the potential for robust T cell responses.

SUBMITTER: Adam J

PROVIDER: S-EPMC3994040 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Abacavir induced T cell reactivity from drug naïve individuals shares features of allo-immune responses.

Adam Jacqueline J Wuillemin Natascha N Watkins Stephan S Jamin Heidi H Eriksson Klara K KK Villiger Peter P Fontana Stefano S Pichler Werner J WJ Yerly Daniel D

PloS one 20140421 4

Abacavir hypersensitivity is a severe hypersensitivity reaction which occurs exclusively in carriers of the HLA-B*57∶01 allele. In vitro culture of PBMC with abacavir results in the outgrowth of abacavir-reacting CD8+ T cells, which release IFNγ and are cytotoxic. How this immune response is induced and what is recognized by these T cells is still a matter of debate. We analyzed the conditions required to develop an abacavir-dependent T cell response in vitro. The abacavir reactivity was indepen ...[more]

PMID: 24751900

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Project description:ObjectivesSurveillance drug resistance mutations (SDRMs) in drug-naive patients are typically used to survey HIV-1-transmitted drug resistance (TDR). We test here how SDRMs in patients failing treatment, the original source of TDR, contribute to assessing TDR, transmissibility and transmission source of SDRMs.DesignThis is a retrospective observational study analyzing a Portuguese cohort of HIV-1-infected patients.MethodsThe prevalence of SDRMs to protease inhibitors, nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) in drug-naive and treatment-failing patients was measured for 3554 HIV-1 subtype B patients. Transmission ratio (prevalence in drug-naive/prevalence in treatment-failing patients), average viral load and robust linear regression with outlier detection (prevalence in drug-naive versus in treatment-failing patients) were analyzed and used to interpret transmissibility.ResultsPrevalence of SDRMs in drug-naive and treatment-failing patients were linearly correlated, but some SDRMs were classified as outliers - above (PRO: D30N, N88D/S, L90?M, RT: G190A/S/E) or below (RT: M184I/V) expectations. The normalized regression slope was 0.073 for protease inhibitors, 0.084 for NRTIs and 0.116 for NNRTIs. Differences between SDRMs transmission ratios were not associated with differences in viral loads.ConclusionThe significant linear correlation between prevalence of SDRMs in drug-naive and in treatment-failing patients indicates that the prevalence in treatment-failing patients can be useful to predict levels of TDR. The slope is a cohort-dependent estimate of rate of TDR per drug class and outlier detection reveals comparative persistence of SDRMs. Outlier SDRMs with higher transmissibility are more persistent and more likely to have been acquired from drug-naive patients. Those with lower transmissibility have faster reversion dynamics after transmission and are associated with acquisition from treatment-failing patients.

Project description:Allopolyploids exhibit both different levels and different patterns of genetic variation than are typical of diploids. However, scant attention has been given to the partitioning of allelic information and diversity in allopolyploids, particularly that among homeologous monoploid components of the hologenome. Sphagnum × falcatulum is a double allopolyploid peat moss that spans a considerable portion of the Holantarctic. With monoploid genomes from three ancestral species, this organism exhibits a complex evolutionary history involving serial inter-subgeneric allopolyploidizations.Studying populations from three disjunct regions [South Island (New Zealand); Tierra de Fuego archipelago (Chile, Argentina); Tasmania (Australia)], allelic information for five highly stable microsatellite markers that differed among the three (ancestral) monoploid genomes was examined. Using Shannon information and diversity measures, the holoploid information, as well as the information within and among the three component monoploid genomes, was partitioned into separate components for individuals within and among populations and regions, and those information components were then converted into corresponding diversity measures.The majority (76 %) of alleles detected across these five markers are most likely to have been captured by hybridization, but the information within each of the three monoploid genomes varied, suggesting a history of recurrent allopolyploidization between ancestral species containing different levels of genetic diversity. Information within individuals, equivalent to the information among monoploid genomes (for this dataset), was relatively stable, and represented 83 % of the grand total information across the Holantarctic, with both inter-regional and inter-population diversification each accounting for about 5 % of the total information.Sphagnum × falcatulum probably inherited the great majority of its genetic diversity at these markers by reticulation, rather than by subsequent evolutionary radiation. However, some post-hybridization genetic diversification has become fixed in at least one regional population. Methodology allowing statistical analysis of any ploidy level is presented.

Dataset Information

Abacavir induced T cell reactivity from drug naive individuals shares features of allo-immune responses.

Publications

Abacavir induced T cell reactivity from drug naïve individuals shares features of allo-immune responses.

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