In silico assessment of binding affinities of three dementia-protective Human Leukocyte Antigen (HLA) alleles to nine human herpes virus antigens

Charonis, Spyros; James, Lisa M.; Georgopoulos, Apostolos P.

doi:10.1016/j.retram.2020.06.002

Cited by 15 publications

(21 citation statements)

References 28 publications

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“…Given the role of Class II HLA in antibody production and host protection against re-exposure to foreign antigens, the finding that dementia prevalence is lower in countries with higher frequency of these alleles suggests that lower dementia rates may be partially attributable to protection against pathogens that bind with these alleles. In fact, a subsequent in silico study revealed that these three dementia alleles were found to bind with significantly higher affinity to herpes virus antigens than were three HLA alleles that are dementia-neutral -DRB1*03:01, DRB1*07:01, DRB1*08:01 22 . In the present study, we extend those findings to investigate the association of the population frequency 21 of HLA -DRB1 dementiaprotective, dementia-neutral alleles to Parkinson's disease population prevalence 2 .…”

Section: Introductionmentioning

confidence: 99%

Shared Human Leukocyte Antigen (HLA) Coverage in dementia and Parkinson’s disease

James¹,

Georgopoulos²

2020

J Neurol Neuromed

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Dementia and Parkinson's disease are the two most common age-related neurodegenerative conditions. Recent studies have identified Human Leukocyte Antigen (HLA) Class II DRB1 alleles that are protective or neutral with respect to dementia. Here we extend those findings to evaluate the association of the population frequency of HLA DRB1 alleles with the prevalence of dementia and Parkinson's disease in14 Continental Western European countries. Nine HLA DRB1 alleles were identified including four that are protective against dementia (DRB1*01:01, DRB1*04:01, DRB1*13:02, DRB1*15:01), three that are neutral (DRB1*03:01, DRB1*07:01, DRB1*08:01), and two susceptibility alleles (DRB1*11:01, DRB1*04:05). Results demonstrated that the population prevalence's of dementia and Parkinson's disease are highly correlated and that the association between the nine DRB1 alleles above and the population prevalence of dementia is highly overlapping with that of Parkinson's disease. These findings suggest a common HLA Class II DRB1 profile. Given the diverse role of HLA Class II alleles in protection from foreign antigens, autoimmunity, and, possibly, neuroprotection, the shared HLA profile between dementia and Parkinson's disease indicates that common immunogenetic mechanisms underlie the pathogenesis and manifestation of these diseases.

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Section: Introductionmentioning

confidence: 99%

Shared Human Leukocyte Antigen (HLA) Coverage in dementia and Parkinson’s disease

James¹,

Georgopoulos²

2020

J Neurol Neuromed

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“…To the best of our knowledge, there have been only a limited number of published studies (by Nguyen et al [12] and Nelde et al [13]) that investigated viral protein binding affinity across a wide range of HLA alleles on a per-allele basis using predictive algorithms. Our present study builds on previous work [3,4] and examines the relationship between two viral proteins of the SARS-CoV-2 proteome and HLA class I antigen presentation, with the results discussed above. Finally, we devised metric (Q P ) to calculate the overall binding affinity of a gene in a specific population by taking into account both the goodness of binding affinities of alleles of a gene and their frequency of occurrence in the population.…”

Section: Discussionmentioning

confidence: 87%

“…There were three major aims in this in silico study, as follows. First, we sought to quantify the binding affinity of suitable fragments (linear epitopes) of the S protein and ORF1ab polyprotein to the 61 HLA class I alleles in an exhaustive manner using the sliding epitope window approach [3,4]; second, we aimed to assess differences in allele binding affinities between the two proteins, among the three HLA class I genes, and their interaction; and third, we sought to assess the distribution of binding affinities across the sequences of the two proteins. The results obtained were clear cut.…”

Section: Discussionmentioning

confidence: 99%

“…As mentioned above, the main objective of this study was to exhaustively assess the binding affinities of HLA class I and II molecules to the SARS-CoV-2 S protein. For that purpose, we used a sliding epitope window approach [3,4] to partition the sequence of the S protein into subsequences of all possible consecutive 10-mers for (e.g., residues S1-S10, S2-S11, …, S1263-S1273) that covered the entire sequence length (1,273 AA). The method is illustrated in Figure 1.…”

Section: Sars-cov-2 S Proteinmentioning

confidence: 99%

“…In a previous study [3], we reported on the relations between SARS-CoV-2 virus spike glycoprotein (S protein) and 66 common HLA class II alleles, investigated using an in silico approach [4] by assessing the binding affinity of epitopes of the S protein to these most commonly occurring alleles (frequency ≥ 0.01).…”

Section: Introductionmentioning

confidence: 99%

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In silico investigation of binding affinities between human leukocyte antigen class I molecules and SARS-CoV-2 virus spike and ORF1ab proteins

2021

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Aim: The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019, a global pandemic. There is hence an urgent need for effective approaches to understand the mechanism of viral interaction with immune cells that lead to viral elimination and subsequent long-term immunity. The first, immediate response to the viral infection involves mobilization of native immunity and human leukocyte antigen (HLA) class I mechanisms to kill infected cells and eliminate the virus. The second line of defense involves the activation of HLA class II system for the production of antibodies against the virus which will add to the elimination of the virus and prevent future infections. In a previous study, investigated the relations between SARS-CoV-2 spike glycoprotein (S protein) and HLA class II alleles were investigaed; here report on the relations of the S protein and the open reading frame 1ab (ORF1ab) of SARS-CoV-2 to HLA class I alleles. Methods: An in silico sliding window approach was used to determine exhaustively the binding affinities of linear epitopes of 10 amino acid length (10-mers) to each of 61 common (global frequency ≥ 0.01) HLA class I molecules (17, 24 and 20 from gene loci A, B and C, respectively). A total of 8,354 epitopes were analyzed; 1,263 from the S protein and 7,091 from ORF1ab. Results: HLA-A genes were the most effective at binding SARS-CoV-2 epitopes for both spike and ORF1ab proteins. Good binding affinities were found for all three genes and were distributed throughout the length of the S protein and ORF1ab polyprotein sequence. Conclusions: Common HLA class I molecules, as a population, are very well suited to binding with high affinity to SARS-CoV-2 spike and ORF1ab proteins and hence should be effective in aiding the early elimination of the virus.

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Negative association between multiple sclerosis immunogenetic profile and in silico immunogenicities of 12 viruses

James,

Georgopoulos

2023

Sci Rep

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Human Leukocyte Antigen (HLA) is involved in both multiple sclerosis (MS) and immune response to viruses. Here we investigated the virus-HLA immunogenicity (V-HLA) of 12 viruses implicated in MS with respect to 17 HLA Class I alleles positively associated to MS prevalence in 14 European countries. Overall, higher V-HLA immunogenicity was associated with smaller MS-HLA effect, with human herpes virus 3 (HHV3), JC human polyoma virus (JCV), HHV1, HHV4, HHV7, HHV5 showing the strongest association, followed by HHV8, HHV6A, and HHV6B (moderate association), and human endogenous retrovirus (HERV-W), HHV2, and human papilloma virus (HPV) (weakest association). These findings suggest that viruses with proteins of high HLA immunogenicity are eliminated more effectively and, consequently, less likely to be involved in MS.

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In silico assessment of binding affinities of three dementia-protective Human Leukocyte Antigen (HLA) alleles to nine human herpes virus antigens

Cited by 15 publications

References 28 publications

Shared Human Leukocyte Antigen (HLA) Coverage in dementia and Parkinson’s disease

Shared Human Leukocyte Antigen (HLA) Coverage in dementia and Parkinson’s disease

In silico investigation of binding affinities between human leukocyte antigen class I molecules and SARS-CoV-2 virus spike and ORF1ab proteins

Negative association between multiple sclerosis immunogenetic profile and in silico immunogenicities of 12 viruses

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