scholarly journals Transmission and accumulation of CTL escape variants drive negative associations between HIV polymorphisms and HLA

2005 ◽  
Vol 201 (6) ◽  
pp. 891-902 ◽  
Author(s):  
Alasdair Leslie ◽  
Daniel Kavanagh ◽  
Isobella Honeyborne ◽  
Katja Pfafferott ◽  
Charles Edwards ◽  
...  
Keyword(s):  
Statistical Power ◽  
Vaccine Development ◽  
Immune Escape ◽  
Cytotoxic T Lymphocyte ◽  
Consensus Sequence ◽  
Population Level ◽  
Hla Class I ◽  
Class I ◽  
Escape Mutation ◽  
Leukocyte Antigen

Human immunodeficiency virus (HIV)-1 amino acid sequence polymorphisms associated with expression of specific human histocompatibility leukocyte antigen (HLA) class I alleles suggest sites of cytotoxic T lymphocyte (CTL)-mediated selection pressure and immune escape. The associations most frequently observed are between expression of an HLA class I molecule and variation from the consensus sequence. However, a substantial number of sites have been identified in which particular HLA class I allele expression is associated with preservation of the consensus sequence. The mechanism behind this is so far unexplained. The current studies, focusing on two examples of “negatively associated” or apparently preserved epitopes, suggest an explanation for this phenomenon: negative associations can arise as a result of positive selection of an escape mutation, which is stable on transmission and therefore accumulates in the population to the point at which it defines the consensus sequence. Such negative associations may only be in evidence transiently, because the statistical power to detect them diminishes as the mutations accumulate. If an escape variant reaches fixation in the population, the epitope will be lost as a potential target to the immune system. These data help to explain how HIV is evolving at a population level. Understanding the direction of HIV evolution has important implications for vaccine development.

scholarly journals ASOSIASI HUMAN LEUKOCYTE ANTIGEN (HLA) KARSINOMA NASOFARING (KNF)

2018 ◽  
Vol 15 (2) ◽  
pp. 52
Author(s):  
F.M. Judajana
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Human Leukocyte Antigen ◽  
B Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Genetic System ◽  
Class I ◽  
Leukocyte Antigen ◽  
Barr Virus

Nasopharyngeal Carcinoma (NPC) is one of the most frequent malignancy disease in Java and the incidence rate at several Hospitalsseems increasing yearly. Prevalence of NCP in Indonesian were 3.9 per 100.000 citizen each year. Eipsten-Barr Virus (EBV) is one of theetiological agents of Nasopharyngeal Carcinoma (NPC) and infected B lymphocyte that cause transformation of it to LymphoblastoidCell Line and expresses several antigens. One of them is known as Latent membrane Protein 2A (LMP2A). These antigens is the maintarget of Cytotoxic T lymphocyte (CTL) in immune system surveillance by recognizing an epitope Human Leukocyte Antigen (HLA)class I complexes which expressed on the target cell surface. Beside EBV, there are other factors that. Research of the HLA class I antigenis one of the immune genetic system that has the ability as genetic sensitivity to the disease. The research in NPC patients is not tobe done to show representative for of population in Indonesia especially in Java. The aim of the study was to know the associationbetween HLA class I profile and NPC patients in Java population and to isolate lymphocyte from peripheral blood 24 NPC patients formicrolymphocytotoxicity test with Terasaki Plate derived from UCLA-USA. The results is significantly associated to HLA – A 24 (RR 2.25),HLA A2 (RR 1.635) and HLA A11 (RR 1.065). Based on these HLA class 1 profile as an immune genetics marker on NPC is one of themost important target. In order to develop EBV vaccine in the future, this is necessary especially for Java Population in Indonesia.

scholarly journals Cytotoxic T-Lymphocyte Escape Mutations Identified by HLA Association Favor Those Which Escape and Revert Rapidly

2012 ◽  
Vol 86 (16) ◽  
pp. 8568-8580 ◽  
Author(s):  
Helen R. Fryer ◽  
John Frater ◽  
Anna Duda ◽  
Duncan Palmer ◽  
Rodney E. Phillips ◽  
...  
Keyword(s):  
T Lymphocyte ◽  
Immune Escape ◽  
Cytotoxic T Lymphocyte ◽  
Population Level ◽  
Escape Mutation ◽  
Cross Sectional ◽  
Hla Association ◽  
Escape Mutants ◽  
Ctl Escape ◽  
The Impact

Identifying human immunodeficiency virus (HIV) immune escape mutations has implications for understanding the impact of host immunity on pathogen evolution and guiding the choice of vaccine antigens. One means of identifying cytotoxic-T-lymphocyte (CTL) escape mutations is to search for statistical associations between mutations and host human leukocyte antigen (HLA) class I alleles at the population level. The impact of evolutionary rates on the strength of such associations is not well defined. Here, we address this topic using a mathematical model of within-host evolution and between-host transmission of CTL escape mutants that predicts the prevalence of escape mutants at the population level. We ask how the rates at which an escape mutation emerges in a host who bears the restricting HLA and reverts when transmitted to a host who does not bear the HLA affect the strength of an association. We consider the impact of these factors when using a standard statistical method to test for an association and when using an adaptation of that method that corrects for phylogenetic relationships. We show that with both methods, the average sample size required to identify an escape mutation is smaller if the mutation escapes and reverts quickly. Thus, escape mutations identified as HLA associated systematically favor those that escape and revert rapidly. We also present expressions that can be used to infer escape and reversion rates from cross-sectional escape prevalence data.

scholarly journals Selective Histocompatibility Leukocyte Antigen (Hla)-A2 Loss Caused by Aberrant Pre-mRNA Splicing in 624mel28 Melanoma Cells

1999 ◽  
Vol 190 (2) ◽  
pp. 205-216 ◽  
Author(s):  
Zhigang Wang ◽  
Francesco M. Marincola ◽  
Licia Rivoltini ◽  
Giorgio Parmiani ◽  
Soldano Ferrone
Keyword(s):  
Hla Class I ◽  
Melanoma Cells ◽  
Class I ◽  
Splice Donor Site ◽  
Immune Recognition ◽  
Translation Efficiency ◽  
Exon 2 ◽  
Leukocyte Antigen ◽  
Allele Loss ◽  
Intron 2

Histocompatibility leukocyte antigen (HLA)-A2 is used as a restricting element to present several melanoma-associated antigen (MAA)-derived peptides to cytotoxic T lymphocytes (CTLs). HLA-A2 antigen is selectively lost in primary melanoma lesions and more frequently in metastases. Only scanty information is available about the molecular mechanisms underlying this abnormality, in spite of its potentially negative impact on the clinical course of the disease and on the outcome of T cell–based immunotherapy. Therefore, in this study we have shown that the selective HLA-A2 antigen loss in melanoma cells 624MEL28 is caused by a splicing defect of HLA-A2 pre-mRNA because of a base substitution at the 5′ splice donor site of intron 2 of the HLA-A2 gene. As a result, HLA-A2 transcripts are spliced to two aberrant forms, one with exon 2 skipping and the other with intron 2 retention. The latter is not translated because of an early premature stop codon in the retained intron. In contrast, the transcript with exon 2 skipping is translated to a truncated HLA-A2 heavy chain without the α1 domain. Such a polypeptide is synthesized in vitro but is not detectable in cells, probably because of the low steady state level of the corresponding mRNA and the low translation efficiency. These results indicate that a single mutational event in an HLA class I gene is sufficient for loss of the corresponding allele. This may account, at least in part, for the high frequency of selective HLA class I allele loss in melanoma cells. Our conclusion emphasizes the need to implement active specific immunotherapy with a combination of peptides presented by various HLA class I alleles. This strategy may counteract the ability of melanoma cells with selective HLA class I allele loss to escape from immune recognition.

scholarly journals Multiple sclerosis: disease modifying therapy and the human leukocyte antigen

2018 ◽  
Vol 76 (10) ◽  
pp. 697-704 ◽  
Author(s):  
Lineu Cesar Werneck ◽  
Paulo José Lorenzoni ◽  
Cláudia Suemi Kamoi Kay ◽  
Rosana Herminia Scola
Keyword(s):  
Multiple Sclerosis ◽  
Human Leukocyte Antigen ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Class I ◽  
Interferon Β ◽  
Leukocyte Antigen ◽  
Specific Subset ◽  
Hla Type ◽  
Disease Modifying

ABSTRACT Objective: To investigate the potential relationship between the human leukocyte antigen (HLA) type (class I and II) and the response to several disease-modifying therapies (DMTs) in patients with multiple sclerosis (MS). Methods: We analyzed clinical data of 87 patients with MS at the beginning and end of each type of DMT including the disease duration, Expanded Disability Status Scale and Multiple Sclerosis Severity Score (MSSS). Genotyping of HLA-DRB1, HLA-DPB1, HLA-DQB1, HLA-A, HLA-B and HLA-C alleles were identified using high-resolution techniques. Statistical correlation between the HLA type and response to DMTs was done using the initial and final MSSS. Results: Statistical relationships (p < 0.05) were found for only 15 of 245 alleles tested. There was a reduction in the MSSS for patients treated with corticosteroids (DRB1*15:01, DPB1*04:01, DQB1*02:01 and DQB1*03:01), azathioprine (DRB1*03:01, DPB1*04:01, DQB1*03:02, DQB1*06:02, HLA-C*07:02), interferon β-1a 22 mcg (DRB1*11:04, DQB1*03:01 and DQB1*03:02), interferon β-1a 30 mcg (DPB1*02:01, HLA-C*05:01) and interferon β-1b (DQB1*02:01). Conclusion: These findings suggest a few relationships between the HLA and response to DMTs in the disability for some types of HLA class I and II alleles in a specific subset of MS patients.

scholarly journals 618 Expanding cancer immunotherapy by exploiting recall immunity – A new co-therapy option for checkpoint inhibitors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A648-A648
Author(s):  
Kathlynn Brown ◽  
Michael McGuire ◽  
Anuja Pande ◽  
Indu Venugopal
Keyword(s):  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Hla Class I ◽  
Tumor Burden ◽  
Class I ◽  
Pancreatic Tumors ◽  
Lymphocyte Response ◽  
Targeting Peptide ◽  
Cytotoxic T Lymphocyte Response

BackgroundImmune checkpoint inhibitors (CIs) have emerged as a revolutionary treatment for several cancer types. Despite significant improvement in prognosis for some patients, there are associated challenges. CIs do not work well on immune-cold tumors, thereby eliciting an insufficient immune response. They are also not as effective in tumors with low mutational burden due to dependance on tumor self-antigens for immune recognition. Therefore, there is a need for a solution to improve the efficacy of CIs to make them applicable to the entire cancer patient population.MethodsTo address this challenge, we have developed a novel immunotherapy capable of delivering previously encountered antigenic peptides specifically to cancer cells and facilitating their presentation through the MHC class I pathway. Our therapy utilizes a synthetic nanoparticle delivery system comprising of three components: a neutral stealth liposome, an encapsulated synthetic immunogenic HLA class I restricted peptide derived from measles virus (MV), and a tumor-targeting peptide on the external surface of the liposome. The targeting peptide results in accumulation of the liposomes specifically inside cancer cells, and facilitates presentation of the MV-derived immunogenic peptides in HLA class I molecules. We refer to this system as TALL (Targeted Antigen Loaded Liposomes). As a result, TALL can generate a strong secondary immune response specifically against the targeted tumor cells in a patient who has been previously vaccinated against or infected by MV. In short, we are attempting to trick the immune system into responding as though the cancer cell is infected with MV without the use of a viral particle. Advantageously, as TALL can provide a potent synthetic antigen specifically to tumor cells, it can convert immune-cold tumors into immune-hot, resulting in a robust cytotoxic T lymphocyte response. Therefore, we conducted pilot studies to determine the efficacy of combining TALL with the anti-PD1 checkpoint inhibitor.ResultsTreatment with TALL alone substantially reduces growth of lung, triple-negative breast, and pancreatic tumors in mice. Treatment with TALL and CI combination therapy showed at least a 10-fold reduction in tumor burden in mice bearing orthotopic breast and pancreatic tumors when compared to using CI treatment alone. The combination treatment also successfully prevented metastasis from occurring.ConclusionsTALL can successfully be used in combination with existing immunotherapies like checkpoint inhibitors, to generate a robust cytotoxic T lymphocyte response directed specifically against the tumor, resulting in a drastic reduction of tumor burden.

Characteristics allelic of Human Leukocyte Antigen class I genotype and association with viral load and CD4 cell count in HIV-1 infected patients, Hanoi 2014 – 2016

2021 ◽  
Vol 31 (4) ◽  
pp. 43-50
Author(s):  
Tran Thi Minh Tam ◽  
Nguyen Thuy Linh ◽  
Phan Ha My ◽  
Nguyen Thi Lan Anh
Keyword(s):  
Viral Load ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Class I ◽  
Cd4 Cell Count ◽  
Leukocyte Antigen ◽  
Cell Counts ◽  
Cd4 Cell Counts ◽  
Cd4 Cell ◽  
Hiv 1

Human Leukocyte Antigen (HLA) class I plays a regulatory role in cellular immune response to HIV-1 infection. The role of HLA alleles in HIV progression via viral load and CD4 cell count is well known. HLA class I is polymorphic and distributed differently by nation. This descriptive cross-sectional study was performed on 303 HIV-1 infected patients in 2014 - 2016, with aims to (i) characterize HLA class I genotype with 4-digit nomenclature and (ii) identify specifc alleles in correlate with CD4 cell counts and HIV viral load. 117 allele genotypes have been identifed, including 28 HLA-A alleles, 54 HLA-B alleles and 35 HLA-C alleles. The results showed that the most prevalent alleles in the population include A*11:01 (30.7%), B*15:02 (15.2%) and C*08:01 (17.1%). The frequency of haplotype created from these alleles is 8.4%. A*02:03, B*46:01 related to gender and ethnicity respectively. In conclusion, the study provided detailed pattern of HLA class I expression in a study population of HIV-1 infected patients and reported for the frst time the associated B*51:01, C*14:02 alleles associated to an increase in CD4 cell counts.

scholarly journals Results of a randomized, double-blind phase II clinical trial of NY-ESO-1 vaccine with ISCOMATRIX adjuvant versus ISCOMATRIX alone in participants with high-risk resected melanoma

2020 ◽  
Vol 8 (1) ◽  
pp. e000410
Author(s):  
Jonathan S Cebon ◽  
Martin Gore ◽  
John F Thompson ◽  
Ian D Davis ◽  
Grant A McArthur ◽  
...  
Keyword(s):  
New York ◽  
High Risk ◽  
Phase Ii ◽  
Immune Escape ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Class I ◽  
Double Positive ◽  
Double Blind ◽  
Hla Class I Molecules

BackgroundTo compare the clinical efficacy of New York Esophageal squamous cell carcinoma-1 (NY-ESO-1) vaccine with ISCOMATRIX adjuvant versus ISCOMATRIX alone in a randomized, double-blind phase II study in participants with fully resected melanoma at high risk of recurrence.MethodsParticipants with resected stage IIc, IIIb, IIIc and IV melanoma expressing NY-ESO-1 were randomized to treatment with three doses of NY-ESO-1/ISCOMATRIX or ISCOMATRIX adjuvant administered intramuscularly at 4-week intervals, followed by a further dose at 6 months. Primary endpoint was the proportion free of relapse at 18 months in the intention-to-treat (ITT) population and two per-protocol populations. Secondary endpoints included relapse-free survival (RFS) and overall survival (OS), safety and NY-ESO-1 immunity.ResultsThe ITT population comprised 110 participants, with 56 randomized to NY-ESO-1/ISCOMATRIX and 54 to ISCOMATRIX alone. No significant toxicities were observed. There were no differences between the study arms in relapses at 18 months or for median time to relapse; 139 vs 176 days (p=0.296), or relapse rate, 27 (48.2%) vs 26 (48.1%) (HR 0.913; 95% CI 0.402 to 2.231), respectively. RFS and OS were similar between the study arms. Vaccine recipients developed strong positive antibody responses to NY-ESO-1 (p≤0.0001) and NY-ESO-1-specific CD4+and CD8+responses. Biopsies following relapse did not demonstrate differences in NY-ESO-1 expression between the study populations although an exploratory study demonstrated reduced (NY-ESO-1)+/Human Leukocyte Antigen (HLA) class I+double-positive cells in biopsies from vaccine recipients performed on relapse in 19 participants.ConclusionsThe vaccine was well tolerated, however, despite inducing antigen-specific immunity, it did not affect survival endpoints. Immune escape through the downregulation of NY-ESO-1 and/or HLA class I molecules on tumor may have contributed to relapse.

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