From continental platform towards rifting of the Tisza Unit in the Late Triassic to Early Cretaceous

The Upper Triassic-Lower Cretaceous successions of the Transdanubian part of the Mecsek and Villany-Bihor Zones of the Tisza Unit have been studied from the lithological, lithostratigraphical, sedimentological, microfossil and microfacies points of view in order to correlate and interpret the significant differences between them and to draw a conclusion about their geological and paleogeographical history. After an overview of the paleogeographical reconstructions of the broader area, the succession of the Mecsek and Villany-Bihor Zones and the debated Mariakemend-Bar Range are introduced. Until the end of the Middle Triassic the study area acted as an entity. The first fundamental difference between the two zones can be recognized in the Late Triassic when marine carbonates were replaced by thick fluvial siliciclastics in the Mecsek Zone, while it is represented only by small, local lenses with a few and thin dolostone intercalations in the Villany Zone. The Mecsek Zone is bordered southward by one of the large listric faults to the north of which very thick siliciclastics developed in the Early to Middle Jurassic, whereas it is highly lacunose in the larger western part of the Villany-Bihor Zone. The break at the base is subaerial, higher in the succession it is shallow submarine. The sediment is silty, occasionally sandy crinoidal limestone of late Early Jurassic or even Middle Jurassic in age. The Upper Jurassic in the Mecsek Zone is composed of deep-water cherty limestone while in the Villany Zone it became a thick, shallowing pelagic limestone with reworked patch reef fragments. It is clear evidence that the Mecsek Zone had a thinned continental crust thanks to the nearby rift zone while in the Villany Zone the crust remained thick. The actualized version of the Plasienka's paleogeographical model (Plasienka 2000) is introduced

Mapping HIV-1 Vaccine Induced T-Cell Responses: Bias towards Less-Conserved Regions and Potential Impact on Vaccine Efficacy in the Step Study

T cell directed HIV vaccines are based upon the induction of CD8+ T cell memory responses that would be effective in inhibiting infection and subsequent replication of an infecting HIV-1 strain, a process that requires a match or near-match between the epitope induced by vaccination and the infecting viral strain. We compared the frequency and specificity of the CTL epitope responses elicited by the replication-defective Ad5 gag/pol/nef vaccine used in the Step trial with the likelihood of encountering those epitopes among recently sequenced Clade B isolates of HIV-1. Among vaccinees with detectable 15-mer peptide pool ELISpot responses, there was a median of four (one Gag, one Nef and two Pol) CD8 epitopes per vaccinee detected by 9-mer peptide ELISpot assay. Importantly, frequency analysis of the mapped epitopes indicated that there was a significant skewing of the T cell response; variable epitopes were detected more frequently than would be expected from an unbiased sampling of the vaccine sequences. Correspondingly, the most highly conserved epitopes in Gag, Pol, and Nef (defined by presence in >80% of sequences currently in the Los Alamos database www.hiv.lanl.gov) were detected at a lower frequency than unbiased sampling, similar to the frequency reported for responses to natural infection, suggesting potential epitope masking of these responses. This may be a generic mechanism used by the virus in both contexts to escape effective T cell immune surveillance. The disappointing results of the Step trial raise the bar for future HIV vaccine candidates. This report highlights the bias towards less-conserved epitopes present in the same vaccine used in the Step trial. Development of vaccine strategies that can elicit a greater breadth of responses, and towards conserved regions of the genome in particular, are critical requirements for effective T-cell based vaccines against HIV-1

HLA-restricted immune responses have driven the evolution of HIV-1 clades

Background. HIV mutates to escape selective pressure from antiretroviral medications and HLA-mediated immune responses. Escape mutations can, but do not necessarily, revert to “wild type” (WT) when the selective pressure is withdrawn. Worldwide, HIV has diversified into numerous clades and recombinant forms, and these variations generally follow geopolitical boundaries. Genetically similar human populations also follow these boundaries, so we hypothesized that population HLA has driven HIV evolution and its diversification into the clades. Methods. HIV isolates from 2 HLA-typed cohorts of antiretroviral-naïve patients were analyzed; these isolates included 107 sequences from Caucasian patients in Australia infected with clade B, and 96 from patients in Durban, Africa, infected with clade C. Polymorphism rates were calculated for each amino acid residue in p24 and p17. Associations between HLA and each amino acid residue (comparing consensus vs all nonconsensus) were quantified using multiple logistic regression models with stepwise selection of HLA class I genotype as covariates. Consensus protein sequences for clades A, B, C, D, F, and G obtained from the Los Alamos HIV database were aligned and compared with the locations of polymorphism and HLA association. Results. In p24 and p17, amino acid polymorphism (> 10% of the isolates differed from consensus) occurred at 50 and 56 residues in the Australian and African sequences, respectively. Of these, 33 were in common. Most of the alternative residues found in the Australian and African cohorts were the consensus amino acids for clades other than B and C, respectively. In each cohort, we found 38 residues with significant (p < 0.05) positive and/or negative associations between HLA and sequence polymorphism. The consensus protein sequences for clades A, B, C, D, F, and G differed at 79 residues. In both cohorts almost all of the polymorphic residues—42 (84%) for Australia and 46 (82%) for Africa—and HLA associations—32 (84%) for Australia and 30 (79%) for Africa—occurred at positions where the clade consensus sequences differed. These distributions were highly significant (Fisher p < 0.0001 for both). Conclusions. After introduction of an HIV variant into a host, CTL-mediated immune pressure drives viral evolution within that host. At a population level we propose that the evolution of clades similarly reflects both founder effects and the selective pressures provided by the population HLA distribution

Consistent Cytotoxic-T-Lymphocyte Targeting of Immunodominant Regions in Human Immunodeficiency Virus across Multiple Ethnicities

Although there is increasing evidence that virus-specific cytotoxic-T-lymphocyte (CTL) responses play an important role in the control of human immunodeficiency virus (HIV) replication in vivo, only scarce CTL data are available for the ethnic populations currently most affected by the epidemic. In this study, we examined the CD8(+)-T-cell responses in African-American, Caucasian, Hispanic, and Caribbean populations in which clade B virus dominates and analyzed the potential factors influencing immune recognition. Total HIV-specific CD8(+)-T-cell responses were determined by enzyme-linked immunospot assays in 150 HIV-infected individuals by using a clade B consensus sequence peptide set spanning all HIV proteins. A total of 88% of the 410 tested peptides were recognized, and Nef- and Gag-specific responses dominated the total response for each ethnicity in terms of both breadth and magnitude. Three dominantly targeted regions within these proteins that were recognized by >90% of individuals in each ethnicity were identified. Overall, the total breadth and magnitude of CD8(+)-T-cell responses correlated with individuals' CD4 counts but not with viral loads. The frequency of recognition for each peptide was highly correlated with the relative conservation of the peptide sequence, the presence of predicted immunoproteasomal cleavage sites within the C-terminal half of the peptide, and a reduced frequency of amino acids that impair binding of optimal epitopes to the restricting class I molecules. The present study thus identifies factors that contribute to the immunogenicity of these highly targeted and relatively conserved sequences in HIV that may represent promising vaccine candidates for ethnically heterogeneous populations