scholarly journals Immune Selection for Altered Antigen Processing Leads to Cytotoxic T Lymphocyte Escape in Chronic HIV-1 Infection

2004 ◽  
Vol 199 (7) ◽  
pp. 905-915 ◽  
Author(s):  
Rika Draenert ◽  
Sylvie Le Gall ◽  
Katja J. Pfafferott ◽  
Alasdair J. Leslie ◽  
Polan Chetty ◽  
...  
Keyword(s):  
T Lymphocyte ◽  
Antigen Processing ◽  
Cytotoxic T Lymphocyte ◽  
Immune Selection ◽  
Ctl Epitopes ◽  
Leukocyte Antigen ◽  
Human Infections ◽  
Flanking Regions ◽  
Hiv 1 ◽  
Restricted Epitope

Mutations within cytotoxic T lymphocyte (CTL) epitopes impair T cell recognition, but escape mutations arising in flanking regions that alter antigen processing have not been defined in natural human infections. In human histocompatibility leukocyte antigen (HLA)-B57+ HIV-infected persons, immune selection pressure leads to a mutation from alanine to proline at Gag residue 146 immediately preceding the NH2 terminus of a dominant HLA-B57–restricted epitope, ISPRTLNAW. Although N-extended wild-type or mutant peptides remained well-recognized, mutant virus–infected CD4 T cells failed to be recognized by the same CTL clones. The A146P mutation prevented NH2-terminal trimming of the optimal epitope by the endoplasmic reticulum aminopeptidase I. These results demonstrate that allele-associated sequence variation within the flanking region of CTL epitopes can alter antigen processing. Identifying such mutations is of major relevance in the construction of vaccine sequences.

scholarly journals Identification of Dominant Optimal HLA-B60- and HLA-B61-Restricted Cytotoxic T-Lymphocyte (CTL) Epitopes: Rapid Characterization of CTL Responses by Enzyme-Linked Immunospot Assay

2000 ◽  
Vol 74 (18) ◽  
pp. 8541-8549 ◽  
Author(s):  
Marcus A. Altfeld ◽  
Alicja Trocha ◽  
Robert L. Eldridge ◽  
Eric S. Rosenberg ◽  
Mary N. Phillips ◽  
...  
Keyword(s):  
T Lymphocyte ◽  
Mononuclear Cells ◽  
Cytotoxic T Lymphocyte ◽  
Hla Class I ◽  
Peripheral Blood Mononuclear ◽  
Antiviral Immune Response ◽  
Ctl Epitopes ◽  
Hla Class I Molecules ◽  
Hiv 1 ◽  
Ctl Responses

ABSTRACT Human immunodeficiency virus type 1 (HIV-1)-specific cytotoxic T-lymphocyte (CTL) responses play a major role in the antiviral immune response, but the relative contribution of CTL responses restricted by different HLA class I molecules is less well defined. HLA-B60 or the related allele B61 is expressed in 10 to 20% of Caucasoid populations and is even more highly prevalent in Asian populations, but yet no CTL epitopes restricted by these alleles have been defined. Here we report the definition of five novel HLA-B60-restricted HIV-1-specific CTL epitopes, using peripheral blood mononuclear cells in enzyme-linked immunospot (Elispot) assays and using CTL clones and lines in cytolytic assays. The dominant HLA-B60-restricted epitope, Nef peptide KEKGGLEGL, was targeted by all eight subjects with B60 and also by both subjects with B61 studied. This study additionally establishes the utility of the Elispot assay as a more rapid and efficient method of defining novel CTL epitopes. This approach will help to define new CTL epitopes that may play an important role in the immune control of HIV-1.

scholarly journals Deep sequencing of the HIV-1 polymerase gene for characterisation of cytotoxic T-lymphocyte epitopes during early and chronic disease stages

2021 ◽  
Author(s):  
Paballo Nkone ◽  
Shayne Loubser ◽  
Thomas C. Quinn ◽  
Andrew D. Redd ◽  
Arshad Ismail ◽  
...  
Keyword(s):  
T Lymphocyte ◽  
Deep Sequencing ◽  
Sanger Sequencing ◽  
Cytotoxic T Lymphocyte ◽  
Sequencing Data ◽  
Subtype C ◽  
Ctl Epitopes ◽  
Significant Difference ◽  
Minority Variant ◽  
Hiv 1

Abstract Background Despite multiple attempts, there is still no effective HIV-1 vaccine available. The HIV-1 polymerase (pol) gene is highly conserved and encodes cytotoxic T-lymphocyte (CTL) epitopes. In this study, deep sequencing was employed for characterisation of HIV-1 Pol CTL epitopes in mostly paired samples obtained during early and chronic stages of infection. Deep sequencing data was then compared to Sanger sequencing data only in samples obtained at baseline. Results Fifty-two participants were enrolled in the study. Their median age was 28 years (interquartile range: 24–32 years) and the majority of participants (92.3%) were female. Illumina minority variant analysis identified a significantly higher number of CTL epitopes (n = 65) compared to epitopes (n = 8) identified through Sanger sequencing. Most of the identified epitopes mapped to reverse transcriptase (RT) and integrase (IN) regardless of the method of sequencing. There was a significantly higher proportion of minority variant epitopes in RT (n = 39, 60.0%) compared to IN (n = 17, 26.2%) and PR (n = 9, 13.8%), p = 0.002 and < 0.0001, respectively. However, no significant difference was observed between the proportion of minority variant epitopes in IN versus PR, p = 0.06. Some epitopes were detected in either early or chronic HIV-1 infection whereas others were detected in both stages. Different distribution patterns of minority variant epitopes were observed in sample pairs; with some increasing or decreasing over time, while others remained constant. Some of the identified epitopes have not been previously reported for HIV-1 subtype C. There were also variants that could not be mapped to reported CTL epitopes in the Los Alamos HIV database. Conclusion Deep sequencing revealed many Pol CTL epitopes, including some not previously reported for HIV-1 subtype C. The findings of this study support the inclusion of RT and IN epitopes in HIV-1 vaccine candidates as these proteins harbour many CTL epitopes. Variants that were not mapped within CTL epitopes could represent new epitopes.

scholarly journals Between-Host Evolution of Cytotoxic T-Lymphocyte Epitopes in Human Immunodeficiency Virus Type 1: an Approach Based on Phylogenetically Independent Comparisons

2004 ◽  
Vol 78 (21) ◽  
pp. 11758-11765 ◽  
Author(s):  
Helen Piontkivska ◽  
Austin L. Hughes
Keyword(s):  
Natural Selection ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Ctl Epitopes ◽  
Term Evolution ◽  
Immunodeficiency Virus ◽  
Host Evolution ◽  
Hiv 1

ABSTRACT In human immunodeficiency virus type 1 (HIV-1), mutations that escape from cytotoxic T-lymphocyte (CTL) recognition have been documented, and sequence analyses have provided indirect support for the hypothesis that natural selection has favored CTL escape mutants within an infected host. In spite of such evidence for within-host selection by CTL, it has been more difficult to determine how natural selection by host CTL has influenced long-term evolution of HIV-1. We used statistical analysis of published HIV-1 genomic sequences to examine the role of natural selection in between-host evolution of CTL epitopes. Based on a phylogenetic analysis, we identified 21 pairs of closely related genomes isolated from different hosts and examined the pattern of nucleotide substitution in genomic regions encoding well-characterized CTL epitopes. The results revealed that certain CTL epitopes have been subject to repeated positive selection across the population, while others are generally conserved. Furthermore, evidence of positive selection was associated with divergence from the canonical epitope sequence and with an enhanced frequency of convergent amino acid sequence changes in CTL epitopes. The results support the hypothesis that CTL-driven selection has been a major factor in the long-term evolution of HIV-1.

scholarly journals Glycan-regulated Antigen Processing of a Protein in the Endoplasmic Reticulum Can Uncover Cryptic Cytotoxic T Cell Epitopes

1998 ◽  
Vol 188 (4) ◽  
pp. 773-778 ◽  
Author(s):  
Philip Wood ◽  
Tim Elliott
Keyword(s):  
Endoplasmic Reticulum ◽  
T Cell ◽  
T Lymphocyte ◽  
Influenza A ◽  
Antigen Processing ◽  
Secretory Pathway ◽  
Cytotoxic T Lymphocyte ◽  
Cytotoxic T Cell ◽  
T Cell Epitopes ◽  
Ctl Epitopes

We and others have shown that influenza A nucleoprotein (NP) targeted to the secretory pathway cannot be processed to yield several cytotoxic T lymphocyte (CTL) epitopes in cell lines that lack the transporter associated with antigen processing (TAP). However, a large COOH-terminal fragment of NP is processed and presented in these cells. Full-length NP is cotranslationally glycosylated in the lumen of the endoplasmic reticulum at two sites distal to the major H2-Kk and H2-Db restricted CTL epitopes, and we show here that pharmacological or genetic inhibition of N-linked glycosylation, leads to the processing and presentation of both these epitopes in a TAP-independent way.

scholarly journals Global Database-Driven Assessment of HIV-1 Adaptation to the Immune Repertoires of Human Populations

2015 ◽  
Vol 89 (20) ◽  
pp. 10693-10695 ◽  
Author(s):  
Aram Karakas ◽  
Zabrina L. Brumme ◽  
Art F. Y. Poon
Keyword(s):  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Human Leukocyte ◽  
Human Populations ◽  
Hla Alleles ◽  
Global Database ◽  
Leukocyte Antigen ◽  
Ctl Escape ◽  
The Relationship ◽  
Hiv 1

Associations between HIV-1 cytotoxic T lymphocyte (CTL) escape mutations and their restricting human leukocyte antigen (HLA) alleles imply that HIV could adapt to divergent HLA repertoires of human populations globally. Using publicly available databases, we examine the relationship between the frequencies of 19 experimentally validated CTL escape mutations in HIV-1 reverse transcriptase and their restricting HLA alleles in 59 countries. From these extensive data, we find evidence of differential HIV adaptations to human populations at only a limited number of the studied epitope sites.

scholarly journals Clustered Mutations in HIV-1 Gag Are Consistently Required for Escape from Hla-B27–Restricted Cytotoxic T Lymphocyte Responses

2001 ◽  
Vol 193 (3) ◽  
pp. 375-386 ◽  
Author(s):  
Anthony D. Kelleher ◽  
Chad Long ◽  
Edward C. Holmes ◽  
Rachel L. Allen ◽  
Jamie Wilson ◽  
...  
Keyword(s):  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Phylogenetic Analyses ◽  
High Viral Load ◽  
Hla B27 ◽  
Gag Protein ◽  
Leukocyte Antigen ◽  
Viral Loads ◽  
Lymphocyte Responses ◽  
Hiv 1

The immune response to HIV-1 in patients who carry human histocompatibility leukocyte antigen (HLA)-B27 is characterized by an immunodominant response to an epitope in p24 gag (amino acids 263–272, KRWIILGLNK). Substitution of lysine (K) or glycine (G) for arginine (R) at HIV-1 gag residue 264 (R264K and R264G) results in epitopes that bind to HLA-B27 poorly. We have detected a R264K mutation in four patients carrying HLA-B27. In three of these patients the mutation occurred late, coinciding with disease progression. In another it occurred within 1 yr of infection and was associated with a virus of syncytium-inducing phenotype. In each case, R264K was tightly associated with a leucine to methionine change at residue 268. After the loss of the cytotoxic T lymphocyte (CTL) response to this epitope and in the presence of high viral load, reversion to wild-type sequence was observed. In a fifth patient, a R264G mutation was detected when HIV-1 disease progressed. Its occurrence was associated with a glutamic acid to aspartic acid mutation at residue 260. Phylogenetic analyses indicated that these substitutions emerged under natural selection rather than by genetic drift or linkage. Outgrowth of CTL escape viruses required high viral loads and additional, possibly compensatory, mutations in the gag protein.

scholarly journals The Majority of Currently Circulating Human Immunodeficiency Virus Type 1 Clade B Viruses Fail To Prime Cytotoxic T-Lymphocyte Responses against an Otherwise Immunodominant HLA-A2-Restricted Epitope: Implications for Vaccine Design

2005 ◽  
Vol 79 (8) ◽  
pp. 5000-5005 ◽  
Author(s):  
Marcus Altfeld ◽  
Todd M. Allen ◽  
Elizabeth T. Kalife ◽  
Nicole Frahm ◽  
Marylyn M. Addo ◽  
...  
Keyword(s):  
Acute Phase ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Consensus Sequence ◽  
Clade B ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Restricted Epitope ◽  
Immunodominant Epitopes

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) mutates to escape immune selection pressure, but there is little evidence of selection mediated through HLA-A2, the dominant class I allele in persons infected with clade B virus. Moreover, HLA-A2-restricted responses are largely absent in the acute phase of infection as the viral load is being reduced, suggesting that circulating viruses may lack immunodominant epitopes targeted through HLA-A2. Here we demonstrate an A2-restricted epitope within Vpr (Vpr59-67) that is targeted by acute-phase HIV-1-specific CD8+ T cells, but only in a subset of persons expressing HLA-A2. Individuals in the acute stage of infection with viruses containing the most common current sequence within this epitope (consensus sequence) were unable to mount epitope-specific T-cell responses, whereas subjects infected with the less frequent I60L variant all developed these responses. The I60L variant epitope was a stronger binder to HLA-A2 and was recognized by epitope-specific T cells at lower peptide concentrations than the consensus sequence epitope. These data demonstrate that HLA-A2 is capable of contributing to the acute-phase cytotoxic T-lymphocyte response in infected subjects, but that most currently circulating viruses lack a dominant immunogenic epitope presented by this allele, and suggest that immunodominant epitopes restricted by common HLA alleles may be lost as the epidemic matures.

scholarly journals Clustering Patterns of Cytotoxic T-Lymphocyte Epitopes in Human Immunodeficiency Virus Type 1 (HIV-1) Proteins Reveal Imprints of Immune Evasion on HIV-1 Global Variation

2002 ◽  
Vol 76 (17) ◽  
pp. 8757-8768 ◽  
Author(s):  
Karina Yusim ◽  
Can Kesmir ◽  
Brian Gaschen ◽  
Marylyn M. Addo ◽  
Marcus Altfeld ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Amino Acid ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Amino Acid Sequences ◽  
Ctl Epitopes ◽  
Ctl Epitope ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The human cytotoxic T-lymphocyte (CTL) response to human immunodeficiency virus type 1 (HIV-1) has been intensely studied, and hundreds of CTL epitopes have been experimentally defined, published, and compiled in the HIV Molecular Immunology Database. Maps of CTL epitopes on HIV-1 protein sequences reveal that defined epitopes tend to cluster. Here we integrate the global sequence and immunology databases to systematically explore the relationship between HIV-1 amino acid sequences and CTL epitope distributions. CTL responses to five HIV-1 proteins, Gag p17, Gag p24, reverse transcriptase (RT), Env, and Nef, have been particularly well characterized in the literature to date. Through comparing CTL epitope distributions in these five proteins to global protein sequence alignments, we identified distinct characteristics of HIV amino acid sequences that correlate with CTL epitope localization. First, experimentally defined HIV CTL epitopes are concentrated in relatively conserved regions. Second, the highly variable regions that lack epitopes bear cumulative evidence of past immune escape that may make them relatively refractive to CTLs: a paucity of predicted proteasome processing sites and an enrichment for amino acids that do not serve as C-terminal anchor residues. Finally, CTL epitopes are more highly concentrated in alpha-helical regions of proteins. Based on amino acid sequence characteristics, in a blinded fashion, we predicted regions in HIV regulatory and accessory proteins that would be likely to contain CTL epitopes; these predictions were then validated by comparison to new sets of experimentally defined epitopes in HIV-1 Rev, Tat, Vif, and Vpr.

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