61 research outputs found
Co-Operative Additive Effects between HLA Alleles in Control of HIV-1
Background: HLA class I genotype is a major determinant of the outcome of HIV infection, and the impact of certain alleles on HIV disease outcome is well studied. Recent studies have demonstrated that certain HLA class I alleles that are in linkage disequilibrium, such as HLA-A*74 and HLA-B*57, appear to function co-operatively to result in greater immune control of HIV than mediated by either single allele alone. We here investigate the extent to which HLA alleles - irrespective of linkage disequilibrium - function co-operatively. Methodology/Principal Findings: We here refined a computational approach to the analysis of >2000 subjects infected with C-clade HIV first to discern the individual effect of each allele on disease control, and second to identify pairs of alleles that mediate ‘co-operative additive’ effects, either to improve disease suppression or to contribute to immunological failure. We identified six pairs of HLA class I alleles that have a co-operative additive effect in mediating HIV disease control and four hazardous pairs of alleles that, occurring together, are predictive of worse disease outcomes (q<0.05 in each case). We developed a novel ‘sharing score’ to quantify the breadth of CD8+ T cell responses made by pairs of HLA alleles across the HIV proteome, and used this to demonstrate that successful viraemic suppression correlates with breadth of unique CD8+ T cell responses (p = 0.03). Conclusions/Significance: These results identify co-operative effects between HLA Class I alleles in the control of HIV-1 in an extended Southern African cohort, and underline complementarity and breadth of the CD8+ T cell targeting as one potential mechanism for this effect
Progression to AIDS in South Africa Is Associated with both Reverting and Compensatory Viral Mutations
We lack the understanding of why HIV-infected individuals in South Africa
progress to AIDS. We hypothesised that in end-stage disease there is a shifting
dynamic between T cell imposed immunity and viral immune escape, which, through
both compensatory and reverting viral mutations, results in increased viral
fitness, elevated plasma viral loads and disease progression. We explored how T
cell responses, viral adaptation and viral fitness inter-relate in South African
cohorts recruited from Bloemfontein, the Free State
(n = 278) and Durban, KwaZulu-Natal
(n = 775). Immune responses were measured by
γ-interferon ELISPOT assays. HLA-associated viral polymorphisms were
determined using phylogenetically corrected techniques, and viral replication
capacity (VRC) was measured by comparing the growth rate of gag-protease
recombinant viruses against recombinant NL4-3 viruses. We report that in
advanced disease (CD4 counts <100 cells/µl), T cell responses narrow,
with a relative decline in Gag-directed responses (p<0.0001). This is
associated with preserved selection pressure at specific viral amino acids
(e.g., the T242N polymorphism within the HLA-B*57/5801 restricted TW10
epitope), but with reversion at other sites (e.g., the T186S polymorphism within
the HLA-B*8101 restricted TL9 epitope), most notably in Gag and suggestive
of “immune relaxation”. The median VRC from patients with CD4 counts
<100 cells/µl was higher than from patients with CD4 counts ≥500
cells/µl (91.15% versus 85.19%,
p = 0.0004), potentially explaining the rise in viral load
associated with disease progression. Mutations at HIV Gag T186S and T242N
reduced VRC, however, in advanced disease only the T242N mutants demonstrated
increasing VRC, and were associated with compensatory mutations
(p = 0.013). These data provide novel insights into the
mechanisms of HIV disease progression in South Africa. Restoration of fitness
correlates with loss of viral control in late disease, with evidence for both
preserved and relaxed selection pressure across the HIV genome. Interventions
that maintain viral fitness costs could potentially slow progression
Comparison of isoprene chemical mechanisms under atmospheric night-time conditions in chamber experiments : Evidence of hydroperoxy aldehydes and epoxy products from NO3 oxidation
The gas-phase reaction of isoprene with the nitrate radical (NO3) was investigated in experiments in the outdoor SAPHIR chamber under atmospherically relevant conditions specifically with respect to the chemical lifetime and fate of nitrato-organic peroxy radicals (RO2). Observations of organic products were compared to concentrations expected from different chemical mechanisms: (1) the Master Chemical Mechanism, which simplifies the NO3 isoprene chemistry by only considering one RO2 isomer; (2) the chemical mechanism derived from experiments in the Caltech chamber, which considers different RO2 isomers; and (3) the FZJ-NO3 isoprene mechanism derived from quantum chemical calculations, which in addition to the Caltech mechanism includes equilibrium reactions of RO2 isomers, unimolecular reactions of nitrate RO2 radicals and epoxidation reactions of nitrate alkoxy radicals. Measurements using mass spectrometer instruments give evidence that the new reactions pathways predicted by quantum chemical calculations play a role in the NO3 oxidation of isoprene. Hydroperoxy aldehyde (HPALD) species, which are specific to unimolecular reactions of nitrate RO2, were detected even in the presence of an OH scavenger, excluding the possibility that concurrent oxidation by hydroxyl radicals (OH) is responsible for their formation. In addition, ion signals at masses that can be attributed to epoxy compounds, which are specific to the epoxidation reaction of nitrate alkoxy radicals, were detected. Measurements of methyl vinyl ketone (MVK) and methacrolein (MACR) concentrations confirm that the decomposition of nitrate alkoxy radicals implemented in the Caltech mechanism cannot compete with the ring-closure reactions predicted by quantum chemical calculations. The validity of the FZJ-NO3 isoprene mechanism is further supported by a good agreement between measured and simulated hydroxyl radical (OH) reactivity. Nevertheless, the FZJ-NO3 isoprene mechanism needs further investigations with respect to the absolute importance of unimolecular reactions of nitrate RO2 and epoxidation reactions of nitrate alkoxy radicals. Absolute concentrations of specific organic nitrates such as nitrate hydroperoxides would be required to experimentally determine product yields and branching ratios of reactions but could not be measured in the chamber experiments due to the lack of calibration standards for these compounds. The temporal evolution of mass traces attributed to product species such as nitrate hydroperoxides, nitrate carbonyl and nitrate alcohols as well as hydroperoxy aldehydes observed by the mass spectrometer instruments demonstrates that further oxidation by the nitrate radical and ozone at atmospheric concentrations is small on the timescale of one night (12gh) for typical oxidant concentrations. However, oxidation by hydroxyl radicals present at night and potentially also produced from the decomposition of nitrate alkoxy radicals can contribute to their nocturnal chemical loss
Régime nobiliaire en région avancée : essai d’un bilan
Cet article ne prétend pas à l’exactitude d’une étude monographique. Il propose plutôt une réflexion sur quelques questions centrales de l’histoire nobiliaire de l’époque moderne, vues à travers l’exemple normand, une série d’hypothèses et non pas des découvertes, des conclusions provisoires plutôt que définitives. Une telle approche peut bien évidemment se discuter, mais me semble justifiée par l’état actuel des études nobiliaires. Il y a trente ans, notre « micro-discipline » disposait de b..
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