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Both slowly progressing and rare class I alleles elicit CTL responses in a large proportion of patients bearing those alleles. (A) Class I-related relative hazard of disease progression is negatively correlated with HLA capacity to elicit CTL responses. In a weighted regression, the slope is highly significantly less than zero. (B) HLA allelic frequency in the cohort is negatively correlated with HLA capacity to elicit CTL responses. In a weighted regression, the slope is highly significantly less than zero. In both regression analyses the numbers of epitopes tested for each class I allele were used as weights in the regression, reflecting greater confidence in an average taken across many epitopes than across few (26).
Source publication
There are significant associations between possession of certain HLA class I alleles and rate of progression to AIDS. Immunological data provide an explanatory mechanism for this relationship. Patients with HLA types associated with rapid disease progression recognize a significantly smaller fraction of their known repertoire of viral epitopes than...
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Background: Given that HIV infection is characterized by rapid and continual seeding of the reservoir and ongoing within-host viral evolution, the HIV reservoir during chronic infection should constitute a heterogeneous population in terms of age, genetics and immune escape mutation burden, which may complicate immunotherapeutic cure approaches. We...
Citations
... In this context, genome-wide association studies have been carried out to decipher host factors involved in the natural protection against HIV disease progression and several candidate genes have been shown to play a role in the disease phenotype 6 . ...
This paper is based on a retrospective longitudinal study on people living with HIV under antiretroviral treatment (ART) where allelic variants (either heterozygous CT genotype or homozygous CC genotype) have been evaluated at position −168 of the promoter region of the protein kinase R (−168/PKR). In general, antiviral effects of interferon are partially mediated by a RNA-dependent protein kinase (PKR) that, once activated, inhibits protein synthesis. Indeed, activation of PKR response can inhibit HIV replication. To explore the role of allelic variants in shaping dynamics of commonly monitored HIV biomarkers, CD4 cells, CD8 cells and HIV-load were modelled within a latent class mixed model (LCMM) to account for participants’ heterogeneity over time. The estimated models identified two sub-groups from CD4 and HIV-load dynamics, revealing better outcomes for subgroups of participants with the heterozygous CT genotype. Heterozygous CT subjects in one of the two identified subgroups exhibited higher increase of CD4 cells and more marked decrease of HIV-load, over time, with respect to the homozygous CC subjects assigned to the same group.
... 8 Cytotoxic T lymphocyte responses elicited towards viruses are specific and enhanced in presence of certain human leukocyte antigen alleles as compared to others and changes in even a single amino acid may have a substantial effect on disease progression. 9,10 A few studies have also reported alleles such as HLA-B*13 and HLA-B*58:01 to be protective in groups of HIV controllers when compared to HIV progressors. 11 Apart from alleles, haplotypes have also been found to be associated with HIV transmission. ...
Background
Human leukocyte antigens (HLA) an important host genetic factor is responsible for influencing human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) transmission and disease progression. Contributions of HLA I and II alleles have not been reported in the Indian population with respect to vertical HIV transmission.
Aim
In the current study we determined the frequencies of HLA class I and class II alleles in a cohort of children exposed to HIV through their mothers.
Method
In this exploratory study children perinatally exposed to HIV-1 who fit the study criteria and had completed 18 month follow-up were typed for HLA class I and class II alleles using polymerase chain reaction combined with sequence-specific oligonucleotides probes (PCR-SSOP) and sequence-specific primer (SSP) method. HLA typing was done in 30 positive and 60 HIV negative children along with confounding factors such as treatment regimens, viral load and CD4 count of the mother, feeding option, etc. SPSS software was used for statistical analysis and online docking tools for in-silico analysis.
Results
HLA-B*40 (p = 0.018) was significantly higher in negative children and was associated with protection, whereas HLA-A*01 (p = 0.05), HLA-B*37 (p = 0.032) and HLA-DRB1*09 (p = 0.017) were associated with transmission. Known protective allele HLA-B*27 was only present in negative children. Many specific haplotypes were exclusively present in the negative children or the positive ones. In-silico analysis was performed to predict the ability of HLA-B*40 to bind to antigenic peptides obtained from HIV-1 sequences in our study group.
Limitations
Small sample size is a concerning limitation of the study. Nonetheless this is a comprehensive study on HLA alleles in HIV exposed Indian children
Conclusion
Our study highlights the contribution of HLA class I and II alleles in the Indian children and further adds to understanding the immunogenetic mechanisms. These can be developed as markers for prediction of infection transmission. The observations also contribute to the database of genetic makeup of our population and can help in designing vaccine strategies.
... With the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-1) virus, Taiwanese researchers have shown HLA-B46 to cause severe symptoms [1]. In human immunodeficiency virus (HIV) epitopes, HLA class I molecules show different reactivity of cytotoxic T lymphocyte (CTL), and it is known that HLA with low reactivity poses a high risk of acquired immunodeficiency syndrome (AIDS) becoming severe [2]. The mechanism by which class I molecules, such as HLA-A, -B, and -C, are involved in the aggravation of viral infections is the viral antigen-presenting part of CTL in cell-mediated immunity. ...
Introduction
Each country's difference in the severity rate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may be explained by the difference in human leukocyte antigen (HLA) class I molecules, which affects the reactivity of cytotoxic T lymphocyte (CTL).
Methods
To clarify the relationship between HLA class I and the severity rate, the binding repertoires of each HLA class I allele to SARS-CoV-2 peptides and the allele frequencies of HLA-A, -B, and -A/B haplotypes in each country were quoted.
Results
HLA-A1 and the number of deaths per million population (severity rate) in each country had an exponential approximation correlation with correlation coefficient R=0.4879. In addition, the correlation between the infected cases per million (infection rate) and the severity rate was linearly approximated, with R=0.7422. Weak HLA-A alleles with a repertoire of under 300 also had an exponential approximation correlation with the severity rate (R=0.5972), whereas there was a linear approximation with the infection rate (R=0.6808). Weak HLA-B alleles of 30 repertoires or less had no correlation with the severity rate (R=-0.1530). The weak HLA-A/B haplotype has a stronger effect on the severity rate than the weak HLA-A alone. Therefore, the simple HLA class I susceptibility index was calculated, and a strong correlation (R=0.7388) of an exponential approximation with the severity rate was obtained.
Conclusions
HLA class I susceptible alleles against COVID-19 increase both infection and severity rate. The weak HLA-A is a major factor of severity rate, whereas the weak -B alone has no correlation. However, the weak HLA-A/B haplotype has a stronger effect on the severity rate than the weak -A alone.
... The HLA-B62 supertype, which is composed largely of HLA-B15 alleles, has previously been associated with outcomes in HIV-infected individuals and in patients with melanoma treated with immune checkpoint inhibitors via separate immune mechanisms. In HIV-infected patients, the HLA-B62 supertype is associated with lower HIV viral load and delayed progression to AIDS [8,9,23,24], a finding attributed to its binding of conserved viral epitopes that are less likely to mutate and escape immune recognition [8]. Given the equivalent infection-related deaths among those patients with and without the HLA-B62 supertype (Table 5), it is possible that a recently identified structural feature of a prominent member of the HLA-B62 supertype is responsible for the observed HCT outcomes [4]. ...
Maximizing the probability of antigen presentation to T cells through diversity in HLAs can enhance immune responsiveness and translate into improved clinical outcomes, as evidenced by the association of heterozygosity and supertypes at HLA class I loci with improved survival in patients with advanced solid tumors treated with immune checkpoint inhibitors. We investigated the impact of HLA heterozygosity, supertypes, and surface expression on outcomes in adult and pediatric patients with acute myeloid leukemia (AML), myelodysplastic syndrome, acute lymphoblastic leukemia, and non-Hodgkin lymphoma who underwent 8/8 HLA-matched, T cell replete, unrelated, allogeneic hematopoietic cell transplant (HCT) from 2000 to 2015 using patient data reported to the Center for International Blood and Marrow Transplant Research. HLA class I heterozygosity and HLA expression were not associated with overall survival, relapse, transplant-related mortality (TRM), disease-free survival (DFS), and acute graft-versus-host disease following HCT. The HLA-B62 supertype was associated with decreased TRM in the entire patient cohort (hazard ratio [HR], 0.79; 95% CI, 0.69 to 0.90; P = .00053). The HLA-B27 supertype was associated with worse DFS in patients with AML (HR = 1.21; 95% CI, 1.10 to 1.32; P = .00005). These findings suggest that the survival benefit of HLA heterozygosity seen in solid tumor patients receiving immune checkpoint inhibition does not extend to patients undergoing allogeneic HCT. Certain HLA supertypes, however, are associated with TRM and DFS, suggesting that similarities in peptide presentation between supertype members play a role in these outcomes. Beyond implications for prognosis following HCT, these findings support the further investigation of these HLA supertypes and the specific immune peptides important for transplant outcomes.
... B*35 subtypes differing in their peptide-binding specificity at position 9 of the peptide binding site were also considered, and it was shown that changes at a single amino acid position of the HLA molecules could lead to differences in terms of HIV disease progression [34]. A significant negative correlation was also observed between the rapidity of AIDS progression and the number of viral epitopes recognised by HLA class I types, suggesting a direct relationship between HLA alleles and the progression of the disease [35]. More recently, Pereyra et al. [36] performed GWAS in a multiethnic cohort of HIV-1 controllers (infected people who show ability to control HIV replication without any therapy and who do not develop clinical disease) and progressors (used as controls): in the largest European group, they identified 313 SNPs reaching genome-wide significance in HLA and none in other genomic regions. ...
Human leucocyte antigen (HLA) alleles and single nucleotide polymorphisms (SNPs) lying in the HLA region are known to be associated with several infectious diseases among which acquired immunodeficiency syndrome, hepatitis B, hepatitis C, tuberculosis, leprosy and malaria are highly prevalent in many human populations worldwide. Distinct approaches such as case-control comparisons, immunogenetic analyses, bioinformatic peptide-binding predictions, ancient DNA and genome-wide association studies (GWAS) have contributed to improving this knowledge during the last decade, although many results still need stronger statistical and/or functional support. The present review updates the information regarding the main HLA allele and SNP associations observed to date for six of the most widespread and some other infectious diseases, and provides a synthetic illustration of these findings on a schematic HLA genomic map. It then discusses these results by stressing the importance of integrating information on HLA population diversity in disease-association studies.
... B4001 B40 D7 A0101 A0201 B3501 B4001 C0304 C0401 EIYKRWIIL GAG 260-268 A2 A0201 A2 D7 A0101 A0201 B3501 B4001 C0304 C0401 YPLTFGWCY NEF 135-143 B35 B3501 B35 D7 A0101 A0201 B3501 B4001 C0304 C0401 RYPLTFGWCY NEF 134-143 ? B3501 B35 D7 A0101 A0201 (Almeida et al., 2007;Scherer et al., 2004;Wilson et al., 2000). ...
... Car dans l'infection naturelle par le VIH-1, les patients du supertype B7 n'ont pas une grande capacité à induire des réponses CTL (Scherer et al., 2004). Ainsi on peut imaginer que la vaccination avec LIPO-5 pourrait permettre de mieux contrôler le virus en permettant l'induction de ces réponses CTL restreintes par la superfamille HLA B7. (Scherer et al., 2004). ...
... Car dans l'infection naturelle par le VIH-1, les patients du supertype B7 n'ont pas une grande capacité à induire des réponses CTL (Scherer et al., 2004). Ainsi on peut imaginer que la vaccination avec LIPO-5 pourrait permettre de mieux contrôler le virus en permettant l'induction de ces réponses CTL restreintes par la superfamille HLA B7. (Scherer et al., 2004). ...
Depuis les années 1990, l’ANRS (France Recherche Nord&Sud Sida-HIV hépatites) a mis en place une stratégie de vaccination anti-VIH-1 originale fondée sur l’utilisation de peptides contenant des épitopes T couplés à une molécule lipidique et capables d’induire des réponses poly-épitopiques. Ces lipopeptides ont la particularité d’induire des réponses cellulaires sans nécessiter d’adjuvant via l’activation du TLR2 par l’acide palmitique composant la queue lipidique de ces lipopeptides qui permet également la cross-présentation d’épitopes T CD8+ par les cellules dendritiques. Le candidat vaccin LIPO-5, constitué de 5 longs peptides (Gag 17-35, Gag 253-284, Nef 66-97, Nef 116-145, et Pol 325-355) comportant différents épitopes T CD8+ et CD4+ du VIH-1 de sous-type B couplés en position C-terminale à un acide monopalmitique via une lysine, est utilisé chez l’homme depuis bientôt 20 ans dans différents essais cliniques de phase I et II.Lors de cette thèse, nous nous sommes focalisés sur l’étude des réponses T CD4+ et CD8+ induites par les vaccins lipopeptidiques développés par l’ANRS et plus particulièrement sur le candidat vaccin LIPO-5, utilisé notamment dans les essais prophylactiques ANRS VAC 18 et VRI 01, et les essais thérapeutiques ANRS LIGHT et DALIA. Nous avons identifié et caractérisé les réponses T CD8+ et CD4+ post-vaccinales lors de l’essai DALIA et comparé ces réponses avec celles observées dans différents essais de vaccination thérapeutique et prophylactique menés par l’ANRS, utilisant des lipopeptides associés ou non à d’autres candidats vaccin (ALVAC, MVA et ADN).Nous avons ainsi pu montrer que l’immunodominance de ces réponses n’était pas modifiée entre volontaires sains et patients infectés par le VIH-1. De plus nous avons montré que l’utilisation du candidat vaccin LIPO-5 en « prime » était particulièrement intéressante pour focaliser les réponses vaccinales sur les régions conservées du VIH-1 intégrées dans ce vaccin, et que le LIPO-5 chargé sur des cellules dendritiques induisait une meilleure immunogénicité, confirmant l’intérêt de ce vaccin pour la stratégie de « DC targeting » ex vivo. Enfin, nous avons également montré que la vaccination lipopeptidique permettait l’induction spécifique d’IL-13 par les LT CD4+ et que cette réponse était associée à un faible rebond viral lors de la phase d’interruption de traitement de l’essai ANRS DALIA.Ces résultats sont importants dans la quête de vaccins prophylactiques et thérapeutiques efficaces contre le VIH-1.
... In contrast, peptide fragments, forming stable complexes with MHC proteins are recognized by T-lymphocytes and the infected cells are destroyed. This explains the inherent resistance to certain diseases [6]. The HLA-DP1 and HLA-DP5 alleles are associated with susceptibility to hyperthyroidism [7,8]; allele HLA-DP2 -with susceptibility to Beryllium disease [9,10], juvenile rheumatoid arthritis [11], sarcoidosis [12], atopic myelitis [13]; allele HLA-DP3with susceptibility to juvenile rheumatoid arthritis [14], allele HLA-DP41 -with protection from celiac disease [15], allele HLA-DP42 -with protection from Beryllium disease [16]. ...
The human leukocyte antigen (HLA) system is an important part of the immune system involved in the presentation of antigen fragments (oligopeptides) to the T-cells. The proteins encoded by the HLA class II genes of locus DP are associated with a significant number of autoimmune diseases, as well as with the susceptibility or resis-tance to a number of infectious agents. The aim of the present study is to analyse the structure – affinity relationships of antigen peptides binding to 7 most common in the human population HLA-DP proteins. The analysis is performed by proteochemometrics. A set of 3,864 15-mer peptides, known binders and non-binders to HLA-DP proteins, are compiled from IEDB. The set is pre-processed and divided into training (80%) and test (20%) subsets. The training set is used to derive a proteochemometric model by iterative self-consistent partial least squares-based algorithm. The derived model has good explaining capacity (R2 = 0.899 and Q2 = 0.892), but moderate predictive ability validated by the test set (Rpred = 0.515). The proteochemometrics is a suitable method for struc-ture-affinity analysis of peptides binding to multiple HLA proteins.
PROTEOCHEMOMETRIC ANALYSIS OF PEPTIDES BINDING TO HUMAN LEUKOCYTE ANTIGEN (HLA) PROTEINS FROM LOCUS DP. Available from: https://www.researchgate.net/publication/324686405_PROTEOCHEMOMETRIC_ANALYSIS_OF_PEPTIDES_BINDING_TO_HUMAN_LEUKOCYTE_ANTIGEN_HLA_PROTEINS_FROM_LOCUS_DP [accessed Jun 06 2018].
... In certain cases, overrepresentation of specific HLA class I alleles (e.g. HLA-B27) is associated with an effective immune response, characterized by HIV-specific T cells with high avidity, polyfunctionality, and capacity to proliferate against both the immunodominant epitopes (e.g. for HLA-B27 the B27-KK10 epitope (KRWIILGLNK at positions 263-272) in p24 Gag) and escape variants thereof [151][152][153]. HLA alleles HLA-B57 and HLA-B5801 also exert strong selection pressure on the virus and are thus associated with long-term HIV control [154]. ...
Etiology, transmission and protection: Transmission of HIV, the causative agent of AIDS, occurs predominantly through bodily fluids. Factors that significantly alter the risk of HIV transmission include male circumcision, condom use, high viral load, and the presence of other sexually transmitted diseases. Pathology/Symptomatology: HIV infects preferentially CD4 + T lym-phocytes, and Monocytes. Because of their central role in regulating the immune response, depletion of CD4 + T cells renders the infected individual incapable of adequately responding to microorganisms otherwise inconsequential. Epidemiology, incidence and prevalence: New HIV infections affect predominantly young heterosexual women and homosexual men. While the mortality rates of AIDS related causes have decreased globally in recent years due to the use of highly active antiretroviral therapy (HAART) treatment, a vaccine remains an elusive goal. Treatment and curability: For those afflicted HIV infection remains a serious illness. Nonetheless, the use of advanced therapeutics have transformed a dire scenario into a chronic condition with near average life spans. When to apply those remedies appears to be as important as the remedies themselves. The high rate of HIV replication and the ability to generate variants are central to the viral survival strategy and major barriers to be overcome. Molecular mechanisms of infection: In this review, we assemble new details on the molecular events from the attachment of the virus, to the assembly and release of the viral progeny. Yet, much remains to be learned as understanding of the molecular mechanisms used in viral repli-cation and the measures engaged in the evasion of immune surveillance will be important to develop effective interventions to address the global HIV pandemic.
... Single-cell assays have uncovered many of the events that follow the acquisition of HIV, including the presence or absence of antigen-specific responses during acute and chronic infection [3][4][5][6], their breadth and magnitude [7,8], and associated phenotypic alterations [9][10][11]. Moreover, they have facilitated the study of viral persistence and evolution [12][13][14] and the identification of protective alleles [15,16] and host restriction factors [17]. Single-molecule studies with tagged reporters that express the green fluorescence protein (GFP) or its variants have also been invariably used in the HIV field to address the dynamics of cellular interactions at molecular level. ...
The use of advanced tissue-imaging methodologies has greatly facilitated the study of molecular mechanisms and cellular interactions in humans and animal models of disease. Particularly, in HIV research, there is an ever-increasing demand for a comprehensive analysis of immune cell dynamics at tissue level stemming from the need to advance our understanding of those interactions that regulate the generation of adaptive antigen-specific immune responses. The latter is critical for the development of vaccines to elicit broadly neutralizing antibodies as well as for the discovery of novel targets for immuno-therapies to strengthen the cytolytic arm of the immune system at local level. In this review, we focus on current and emerging imaging technologies, discuss their strengths and limitations, and examine how such technologies can inform the development of new treatments and vaccination strategies. We also present some perspective on the future of the technology development.
... However, it is clear that viral adaptation outside of env (e.g. escape from CTL immune responses[48]) is important in determining variation in viral replication and disease progression. Therefore our results should not be used to support the inverse argument, i.e. that env adaptation rates explain variation in viral load. ...
Author
Since some common approaches to the study of molecular adaptation may not be optimal for answering questions regarding within-host virus evolution, we have developed an alternative approach that estimates an absolute rate of molecular adaptation from serially-sampled viral populations. Here, we extend this framework to include sampling error when estimating the rate of adaptation, which is an important addition when analyzing historical data sets obtained in the pre-HAART era, for which the number of sequences per time point is often limited. We applied this extended method to a cohort of 24 pediatric HIV-1 patients and discovered that viral adaptation is strongly associated with the rate of disease progression, which is in contrast to previous analyses of these data that did not find a significant association. Strikingly, this results in a negative relationship between the rate of viral adaptation and viral population size, which is unexpected under standard micro-evolutionary models since larger populations are predicted to fix more mutations per unit time than smaller populations. Our findings indicate that the negative correlation is unlikely to be driven by relaxation of selective constraint, but instead by significant variation in host immune responses. Consequently, this supports a previously proposed non-linear model of viral adaptation in which host immunity imposes counteracting effects on population size and selection.
