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Srinika Ranasinghe, Pedro A Lamothe, Damien Z Soghoian, Samuel W Kazer, Michael B Cole, Alex K Shalek, Nir Yosef, R Brad Jones, Faith Donaghey, Chioma Nwonu, Priya Jani, Gina M Clayton, Frances Crawford, Janice White, Alana Montoya, Karen Power, Todd M Allen, Hendrik Streeck, Daniel E Kaufmann, Louis J Picker, John W Kappler, Bruce D Walker
CD8(+) T cell recognition of virus-infected cells is characteristically restricted by major histocompatibility complex (MHC) class I, although rare examples of MHC class II restriction have been reported in Cd4-deficient mice and a macaque SIV vaccine trial using a recombinant cytomegalovirus vector. Here, we demonstrate the presence of human leukocyte antigen (HLA) class II-restricted CD8(+) T cell responses with antiviral properties in a small subset of HIV-infected individuals. In these individuals, T cell receptor β (TCRβ) analysis revealed that class II-restricted CD8(+) T cells underwent clonal expansion and mediated killing of HIV-infected cells...
October 18, 2016: Immunity
Stephen A Migueles, Mark Connors
CD8(+) T cells that recognize peptides presented by MHC class II molecules have been observed in a macaque SIV vaccine model. A new study by Ranasinghe et al. (2016) shows that virus-specific class-II-restricted CD8(+) T cells can be found in some HIV-infected patients.
October 18, 2016: Immunity
Angela Berzi, Stefania Ordanini, Ben Joosten, Daria Trabattoni, Alessandra Cambi, Anna Bernardi, Mario Clerici
DC-SIGN, a C-type lectin mainly expressed by DCs, mediates antigen uptake and can induce specific immune responses, depending on the ligand involved. Owing to these properties, DC-SIGN is an attracting target for approaches aimed at tailoring the immune response towards specific immunologic outcomes. A multivalent DC-SIGN ligand (Polyman26), containing at its core a fluorescent "rod-like" spacer and able to inhibit DC-SIGN mediated HIV infection in nanomolar concentration, has been recently developed by our group...
October 13, 2016: Scientific Reports
Nicholas J Maness
Decades of research, including the 1996 Nobel Prize in Medicine, confirm the evolutionary and immunological importance of CD8 T lymphocytes (TCD8+) that target peptides bound by the highly variable major histocompatibility complex class I (MHC-I) proteins. However, their perceived importance has varied dramatically over the past decade. Regardless, there remains myriad reasons to consider the diversity of MHC-I alleles and the TCD8+ that target them as enormously important in infectious disease research. Thus, understanding these molecules in the best animal models of human disease could be a necessity for optimizing the translational potential of these models...
October 11, 2016: Toxicologic Pathology
Catharina D Prinsloo, Minrie Greeff, Annamarie Kruger, Suria Ellis
The purpose of the research was to determine whether an HIV stigma-reduction community "hub" network intervention in a South African urban area would bring about a difference in the psychosocial well-being of people living with HIV (PLWH), as well as their community (living in the same municipal ward). A single case pre-test post-test design was implemented. The sample for this study included 62 PLWH who were selected through accessibility sampling and 570 community members who were selected through random voluntary sampling...
September 2016: African Journal of AIDS Research: AJAR
Emily B Wong, Thumbi Ndung'u, Victoria O Kasprowicz
Mucosal associated invariant T (MAIT) cells are donor-unrestricted lymphocytes that are surprisingly abundant in humans, representing 1-10% of circulating T cells and further enriched in mucosal tissues. MAIT cells recognize and are activated by small molecule ligands produced by microbes and presented by MR1, a highly conserved MHC-related antigen presenting protein that is ubiquitously expressed in human cells. Increasing evidence suggests that MAIT cells play a protective role in anti-bacterial immunity at mucosal interfaces...
September 16, 2016: Immunology
Nischal Ranganath, Teslin S Sandstrom, Saleh Fadel, Sandra C Côté, Jonathan B Angel
BACKGROUND: The latent HIV-1 reservoir represents the primary barrier to the eradication of HIV-1 infection. The design of novel reservoir-clearance strategies, however, is impeded in part by the inability to distinguish latently HIV-infected cells from uninfected cells. Significant impairment of the type I interferon (IFN-I) response is observed during productive HIV-1 infection. Although this remains poorly described in the context of latent HIV-1 infection, presence of potential defects may serve as a novel therapeutic target...
2016: Retrovirology
Chintan H Kapadia, Shaomin Tian, Jillian L Perry, J Christopher Luft, Joseph M DeSimone
Educating our immune system via vaccination is an attractive approach to combat infectious diseases. Eliciting antigen specific cytotoxic T cells (CTLs), CD8(+) effector T cells, is essential in controlling intracellular infectious diseases such as influenza (Flu), tuberculosis (TB), hepatitis, and HIV/AIDS, as well as tumors. However, vaccination utilizing subunit peptides to elicit a potent CD8(+) T cell response with antigenic peptides is typically ineffective due to poor immunogenicity. Here we have engineered a reduction sensitive nanoparticle (NP) based subunit vaccine for intracellular delivery of an antigenic peptide and immunostimulatory adjuvant...
October 3, 2016: Molecular Pharmaceutics
Dürdal Us
Superantigens (SAgs) are microbial proteins produced by various microorganisms that elicit excessive and strong stimulation of T cells via an unconventional mechanism. They cause polyclonal activation of T cells in a non-specific manner, by binding to a particular variable-beta (Vβ) chain of T-cell receptor (TCR) and MHC class II molecule, in unprocessed form and outside of peptide-binding cleft, forming a bridge between the antigen presenting cell and the T cell. SAgs are classified into three groups, namely 1) exogenous (soluble proteins and exotoxins secreted by microorganisms), 2) endogenous (transmembrane proteins encoded by viruses which are integrated into the genome) and 3) B-cell SAgs (proteins which stimulate predominantly B cells)...
July 2016: Mikrobiyoloji Bülteni
Tetsuo Tsukamoto, Hiroyuki Yamamoto, Seiji Okada, Tetsuro Matano
Although antiretroviral therapy has made human immunodeficiency virus (HIV) infection a controllable disease, it is still unclear how viral replication persists in untreated patients and causes CD4(+) T-cell depletion leading to acquired immunodeficiency syndrome (AIDS) in several years. Theorists tried to explain it with the diversity threshold theory in which accumulated mutations in the HIV genome make the virus so diverse that the immune system will no longer be able to recognize all the variants and fail to control the viraemia...
September 2016: Medical Hypotheses
Joseph S Murray, Elaina H Murray
Genes of the major histocompatibility complex (MHC; also called HLA in human) are polymorphic elements in the genomes of sharks to humans. Class-I and class-II MHC loci appear responsible for much of the genetic linkage to myriad disease states via the capacity to bind short (~8-15 a.a.) peptides of a given pathogen's proteome, or in some cases, the altered proteomes of cancerous cells, and even (in autoimmunity) certain nominal 'self' peptides (Janeway, 2004).(1) Unfortunately, little is known about how the canonical structure of the MHC-I/-II peptide-presenting gene evolved, particularly since beyond ~500 Mya (sharks) no paralogs exist...
May 2016: Mobile Genetic Elements
Laura Emily Hudson, Rachel Louise Allen
MHC class I (MHC-I) polymorphisms are associated with the outcome of some viral infections and autoimmune diseases. MHC-I proteins present antigenic peptides and are recognized by receptors on natural killer cells and cytotoxic T lymphocytes, thus enabling the immune system to detect self-antigens and eliminate targets lacking self or expressing foreign antigens. Recognition of MHC-I, however, extends beyond receptors on cytotoxic leukocytes. Members of the leukocyte Ig-like receptor (LILR) family are expressed on monocytic cells and can recognize both classical and non-classical MHC-I alleles...
2016: Frontiers in Immunology
Marijana Rucevic, Georgio Kourjian, Julie Boucau, Renata Blatnik, Wilfredo Garcia Bertran, Matthew J Berberich, Bruce D Walker, Angelika B Riemer, Sylvie Le Gall
UNLABELLED: Despite the critical role of epitope presentation for immune recognition, we still lack a comprehensive definition of HIV peptides presented by HIV-infected cells. Here we identified 107 major histocompatibility complex (MHC)-bound HIV peptides directly from the surface of live HIV-transfected 293T cells, HIV-infected B cells, and primary CD4 T cells expressing a variety of HLAs. The majority of peptides were 8 to 12 amino acids (aa) long and mostly derived from Gag and Pol...
October 1, 2016: Journal of Virology
H Hamlet Chu, Shiao-Wei Chan, John Paul Gosling, Nicolas Blanchard, Alexandra Tsitsiklis, Grant Lythe, Nilabh Shastri, Carmen Molina-París, Ellen A Robey
Highly functional CD8(+) effector T (Teff) cells can persist in large numbers during controlled persistent infections, as exemplified by rare HIV-infected individuals who control the virus. Here we examined the cellular mechanisms that maintain ongoing T effector responses using a mouse model for persistent Toxoplasma gondii infection. In mice expressing the protective MHC-I molecule, H-2L(d), a dominant T effector response against a single parasite antigen was maintained without a contraction phase, correlating with ongoing presentation of the dominant antigen...
July 19, 2016: Immunity
Johanna M Eberhard, Fareed Ahmad, Henoch S Hong, Nupur Bhatnagar, Phillip Keudel, Julian Schulze Zur Wiesch, Reinhold E Schmidt, Dirk Meyer-Olson
BACKGROUND: Immune senescence as well as disturbed CD8(+) T cell differentiation are a hallmark of chronic HIV infection. Here, we investigated to what extent immune senescence is reversible after initiation of antiretroviral treatment (ART). METHODS: PBMCs from a cohort of HIV patients with different disease courses including untreated viral controllers (n=10), viral non-controllers (n=16) and patients on anti-retroviral therapy (ART) (n=20), were analyzed and compared to uninfected controls (n=25) by flow cytometry on bulk and HIV-specific MHC class I tetramer(+) CD8(+) T cells for expression of the memory markers CCR7, CD45RO, as well as the senescence marker CD57 and the differentiation and survival marker CD127...
July 5, 2016: Clinical and Experimental Immunology
Peter van Endert
Cross-presentation of internalized antigens by dendritic cells requires efficient delivery of Major Histocompatibility Complex (MHC) class I molecules to peptide-loading compartments. Strong evidence suggests that such loading can occur outside of the endoplasmic reticulum; however, the trafficking pathways and sources of class I molecules involved are poorly understood. Examination of non-professional, non-phagocytic cells has revealed a clathrin-independent, Arf6-dependent recycling pathway likely traveled by internalized optimally loaded (closed) class I molecules...
July 2016: Immunological Reviews
Debbie Ferguson, Sean Clarke, Neil Berry, Neil Almond
OBJECTIVES: Using simian models where SIV chronic viral loads are naturally controlled in the absence of potentially neurotoxic therapies we investigated the neuropathological events occurring during times of suppressed viremia and when these events were initiated. DESIGN: Cynomolgus macaques were infected with SIV strains that are naturally controlled to low levels of chronic viremia. Study one; animals were maintained upto 300 days post inoculation and analysed for viral induced neuropathology following sustained suppression of chronic viral loads...
June 1, 2016: AIDS
Xiaoming Sun, Yi Shi, Tomohiro Akahoshi, Mamoru Fujiwara, Hiroyuki Gatanaga, Christian Schönbach, Nozomi Kuse, Victor Appay, George F Gao, Shinichi Oka, Masafumi Takiguchi
The mechanistic basis for the progressive accumulation of Y(135)F Nef mutant viruses in the HIV-1-infected population remains poorly understood. Y(135)F viruses carry the 2F mutation within RW8 and RF10, which are two HLA-A(∗)24:02-restricted superimposed Nef epitopes recognized by distinct and adaptable CD8(+) T cell responses. We combined comprehensive analysis of the T cell receptor repertoire and cross-reactive potential of wild-type or 2F RW8- and RF10-specific CD8(+) T cells with peptide-MHC complex stability and crystal structure studies...
June 7, 2016: Cell Reports
Melanie Friedrich, Christian Setz, Friedrich Hahn, Alina Matthaei, Kirsten Fraedrich, Pia Rauch, Petra Henklein, Maximilian Traxdorf, Torgils Fossen, Ulrich Schubert
The HIV-1 Gag p6 protein regulates the final abscission step of nascent virions from the cell membrane by the action of its two late (L-) domains, which recruit Tsg101 and ALIX, components of the ESCRT system. Even though p6 consists of only 52 amino acids, it is encoded by one of the most polymorphic regions of the HIV-1 gag gene and undergoes various posttranslational modifications including sumoylation, ubiquitination, and phosphorylation. In addition, it mediates the incorporation of the HIV-1 accessory protein Vpr into budding virions...
April 2016: Viruses
Daniela Benati, Moran Galperin, Olivier Lambotte, Stéphanie Gras, Annick Lim, Madhura Mukhopadhyay, Alexandre Nouël, Kristy-Anne Campbell, Brigitte Lemercier, Mathieu Claireaux, Samia Hendou, Pierre Lechat, Pierre de Truchis, Faroudy Boufassa, Jamie Rossjohn, Jean-François Delfraissy, Fernando Arenzana-Seisdedos, Lisa A Chakrabarti
The rare patients who are able to spontaneously control HIV replication in the absence of therapy show signs of a particularly efficient cellular immune response. To identify the molecular determinants that underlie this response, we characterized the T cell receptor (TCR) repertoire directed at Gag293, the most immunoprevalent CD4 epitope in the HIV-1 capsid. HIV controllers from the ANRS CODEX cohort showed a highly skewed TCR repertoire that was characterized by a predominance of TRAV24 and TRBV2 variable genes, shared CDR3 motifs, and a high frequency of public clonotypes...
June 1, 2016: Journal of Clinical Investigation
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