MHC-I peptides get out of the groove and enable a novel mechanism of HIV-1 escape

Major histocompatibility complex class I (MHC-I) molecules play a crucial role in immunity by capturing peptides for presentation to T cells and natural killer (NK) cells. The peptide termini are tethered within the MHC-I antigen-binding groove, but it is unknown whether other presentation modes occur. Here we show that 20% of the HLA-B*57:01 peptide repertoire comprises N-terminally extended sets characterized by a common motif at position 1 (P1) to P2. Structures of HLA-B*57:01 presenting N-terminally extended peptides, including the immunodominant HIV-1 Gag epitope TW10 (TSTLQEQIGW), showed that the N terminus protrudes from the peptide-binding groove. The common escape mutant TSNLQEQIGW bound HLA-B*57:01 canonically, adopting a dramatically different conformation than the TW10 peptide. This affected recognition by killer cell immunoglobulin-like receptor (KIR) 3DL1 expressed on NK cells. We thus define a previously uncharacterized feature of the human leukocyte antigen class I (HLA-I) immunopeptidome that has implications for viral immune escape. We further suggest that recognition of the HLA-B*57:01-TW10 epitope is governed by a 'molecular tension' between the adaptive and innate immune systems

HIV envelope protein inhibits MHC class I presentation of a cytomegalovirus protective epitope.

CTL recognize peptides that derive from viral protein Ags by proteolytic processing and are presented by MHC class I molecules. In this study we tested whether coexpression of viral Ags in the same cell leads to competition between them. To this end, two L(d)-restricted epitopes derived from HIV-1 envelope gp160 (ENV) and from CMV pp89 phosphoprotein were coexpressed. HIV ENV strain IIIB, but not MN variant, impaired recognition by specific CTL of CMV pp89 epitope 9pp89. Susceptibility to inhibition after ENV coexpression was inversely related to the amount of antigenic 9pp89 peptide processed from different antigenic constructs. In line with it, competition decreased the yield of naturally processed antigenic 9pp89 peptide bound to MHC class I molecules in coinfected cells. Also, point mutants of the presenting MHC class I molecule differed in their competition pattern. Collectively, the data imply that competition operates at the step of MHC-peptide complex assembly or stabilization. We conclude that, although not the rule, in certain combinations there is interference between different Ags expressed in the same cell and presented by the same MHC class I allele. These studies have implications for vaccine development and for understanding immunodominance.This work was supported by grants BIO2-CT92-0177 and BIO4-CT97-0505 from the European Union, PM92-0198, PB94-1261, and PM99-0022 from Dirección General de Investigación Científica y Tecnológica, BIO95-1362-CE from Comisión Interministerial de Ciencia y Tecnología, and AE119/95 from Comunidad de MadridS

Ikskile’s transformations and their reflections in virtual space

Maģistra darba „Ikšķiles transformācijas un to atspoguļojums virtuālā telpā” mērķis ir noskaidrot vietas transformācijas izpausmes Ikšķiles pilsētā un lauku teritorijā, kā arī analizēt to cilvēku uztverē un atspoguļojumu virtuālā telpā. Maģistra darba tēmas izvēle ir saistīta ar Ikšķiles kā vietas un telpas straujo attīstību Rīgas pilsētas pievārtē, pieaugošo moderno tehnoloģiju lomu cilvēku ikdienā, kā arī ar autora profesionālo darbību Ikšķiles novadā - gandrīz desmit gadus autors ir strādājis mērniecības jomā. Maģistra darbs rakstīts ar mērķi izpētīt vietas transformācijas izpausmes no cilvēka ģeogrāfijas konceptuālā skatījuma, lielo pilsētu reģionu ietekmē, analizēt ietekmes un atspoguļojumu virtuālā telpā.Master`s thesis „ Ikskile’s transformations and their reflections in virtual space” purpose is to elucidate expressions of place transformations in Ikskile and rural areas, analyze the perception of space transformations and it`s reflections in virtual space. The Masters theme is based on Ikskile`s space rapid development on the outskirts of Riga and the increasing role of modern technologies in everyday life. Based on the experience of the author`s professional activities in Ikskile – nearly ten years author has worked in the sphere of field surveying. The Masters Paper aim is to explore place transformations expressions from conceptual view of human geography, taking into context the influence of growth and development of major urban areas, analyze impact and reflections in virtual space