Sequence-Based Human Leukocyte Antigen—B Typing of Patients Infected with Ebola Virus in Uganda in 2000: Identification of Alleles Associated with Fatal and Nonfatal Disease Outcomes

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Abstract

The Sudan species of Ebola virus (SEBOV) causes severe, often fatal infection in ∼50% of infected humans. We sought to determine whether the human leukocyte antigen—B (HLA-B) locus has a role in the outcome of SEBOV disease by typing 77 cases from an outbreak in northern Uganda in 2000–2001. Sequence-based HLA-B typing was performed using leukocytes isolated from 77 patients. Statistical analysis and a predictive discriminant analysis (PDA) were applied to typing data. Epitope prediction software was also applied to SEBOV sequences. Statistically significant associations were found between certain sets of alleles and either fatal or nonfatal disease outcomes. Alleles B*67 and B*15 were associated with fatal outcomes, whereas B*07 and B*14 were associated with nonfatal outcomes. The PDA-derived functions that were produced were 81.8% accurate in classifying patients into their correct outcome group. Several epitopes predicted to bind strongly to HLA-B*07 molecules were identified in the viral polymerase, nucleoprotein, and VP35 protein. HLA-B alleles associated with either fatal or nonfatal outcomes of SEBOV disease were identified and can be used in a predictive model. Studies of HLA-B—restricted epitopes could contribute to characterization of protective host responses and to vaccine development.

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Most cited references 41

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HLA B*5701 is highly associated with restriction of virus replication in a subgroup of HIV-infected long term nonprogressors.

S. A. Migueles, M Sabbaghian, W Shupert … (2000)

A unique cohort of HIV-1-infected long term nonprogressors (LTNP) with normal CD4(+) T cell counts and <50 copies/ml of plasma were prospectively recruited for study. HLA typing revealed a dramatic association between the HLA B*5701 class I allele and nonprogressive infection [85% (11 of 13) vs. 9.5% (19 of 200) in progressors; P < 0. 001]. Antigen-specific CD8(+) T cells were enumerated by flow cytometric detection of intracellular IFN-gamma in response to HIV antigens and HLA B*57-gag tetramer staining. No quantitative differences in the total HIV-specific CD8(+) T cell responses were observed between B*57(+) LTNP and five B*57(+) progressors (P = 0.4). Although similar frequencies of peptide specific CD8(+) T cells were also found, the gag-specific CD8(+) T cell response in the LTNP group was highly focused on peptides previously shown to be B*57-restricted. These findings indicate that, within this phenotypically and genotypically distinct cohort, a host immune factor is highly associated with restriction of virus replication and nonprogressive disease. They also strongly suggest a mechanism of virus specific immunity that directly operates through the B*5701 molecule. Further characterization of qualitative differences in the virus-specific responses that distinguish HLA B*57(+) LTNP from progressors may ultimately define mechanisms of effective immune mediated restriction of virus replication.

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Scheme for ranking potential HLA-A2 binding peptides based on independent binding of individual peptide side-chains.

K. Parker, M. A. Bednarek, J Coligan (1994)

A method to predict the relative binding strengths of all possible nonapeptides to the MHC class I molecule HLA-A2 has been developed based on experimental peptide binding data. These data indicate that, for most peptides, each side-chain of the peptide contributes a certain amount to the stability of the HLA-A2 complex that is independent of the sequence of the peptide. To quantify these contributions, the binding data from a set of 154 peptides were combined together to generate a table containing 180 coefficients (20 amino acids x 9 positions), each of which represents the contribution of one particular amino acid residue at a specified position within the peptide to binding to HLA-A2. Eighty peptides formed stable HLA-A2 complexes, as assessed by measuring the rate of dissociation of beta 2m. The remaining 74 peptides formed complexes that had a half-life of beta 2m dissociation of less than 5 min at 37 degrees C, or did not bind to HLA-A2, and were included because they could be used to constrain the values of some of the coefficients. The "theoretical" binding stability (calculated by multiplying together the corresponding coefficients) matched the experimental binding stability to within a factor of 5. The coefficients were then used to calculate the theoretical binding stability for all the previously identified self or antigenic nonamer peptides known to bind to HLA-A2. The binding stability for all other nonamer peptides that could be generated from the proteins from which these peptides were derived was also predicted. In every case, the previously described HLA-A2 binding peptides were ranked in the top 2% of all possible nonamers for each source protein. Therefore, most biologically relevant nonamer peptides should be identifiable using the table of coefficients. We conclude that the side-chains of most nonamer peptides to the first approximation bind independently of one another to the HLA-A2 molecule.

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Association of HLA class I with severe acute respiratory syndrome coronavirus infection

Marie Lin, Hsiang-Kuang Tseng, Jean Trejaut … (2003)

Background The human leukocyte antigen (HLA) system is widely used as a strategy in the search for the etiology of infectious diseases and autoimmune disorders. During the Taiwan epidemic of severe acute respiratory syndrome (SARS), many health care workers were infected. In an effort to establish a screening program for high risk personal, the distribution of HLA class I and II alleles in case and control groups was examined for the presence of an association to a genetic susceptibly or resistance to SARS coronavirus infection. Methods HLA-class I and II allele typing by PCR-SSOP was performed on 37 cases of probable SARS, 28 fever patients excluded later as probable SARS, and 101 non-infected health care workers who were exposed or possibly exposed to SARS coronavirus. An additional control set of 190 normal healthy unrelated Taiwanese was also used in the analysis. Results Woolf and Haldane Odds ratio (OR) and corrected P-value (Pc) obtained from two tails Fisher exact test were used to show susceptibility of HLA class I or class II alleles with coronavirus infection. At first, when analyzing infected SARS patients and high risk health care workers groups, HLA-B*4601 (OR = 2.08, P = 0.04, Pc = n.s.) and HLA-B*5401 (OR = 5.44, P = 0.02, Pc = n.s.) appeared as the most probable elements that may be favoring SARS coronavirus infection. After selecting only a "severe cases" patient group from the infected "probable SARS" patient group and comparing them with the high risk health care workers group, the severity of SARS was shown to be significantly associated with HLA-B*4601 (P = 0.0008 or Pc = 0.0279). Conclusions Densely populated regions with genetically related southern Asian populations appear to be more affected by the spreading of SARS infection. Up until recently, no probable SARS patients were reported among Taiwan indigenous peoples who are genetically distinct from the Taiwanese general population, have no HLA-B* 4601 and have high frequency of HLA-B* 1301. While increase of HLA-B* 4601 allele frequency was observed in the "Probable SARS infected" patient group, a further significant increase of the allele was seen in the "Severe cases" patient group. These results appeared to indicate association of HLA-B* 4601 with the severity of SARS infection in Asian populations. Independent studies are needed to test these results.

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Author and article information

Journal

Journal ID (nlm-ta): J Infect Dis

Journal ID (iso-abbrev): J. Infect. Dis

Journal ID (hwp): jinfdis

Journal ID (publisher-id): jid

Title: The Journal of Infectious Diseases

Publisher: The University of Chicago Press

ISSN (Print): 0022-1899

ISSN (Electronic): 1537-6613

Publication date (Print): 15 November 2007

Publication date (Electronic): 15 November 2007

Publication date PMC-release: 15 November 2007

Volume: 196

Issue: Suppl 2

Pages: S329-S336

Affiliations

Special Pathogens Branch, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention , Atlanta, Georgia

Author notes

Reprints or correspondence: Dr. Anthony Sanchez, Special Pathogens Branch, Div. of Viral and Rickettsial Diseases, Centers for Disease Control and Prevention, 1600 Clifton Rd. NE, Mailstop G-14, Atlanta, Georgia 30333 ( ans1@ 123456cdc.gov ).

[a]

Present affiliation: Center for Health Sciences, Ithaca College, Ithaca, New York.

Article

DOI: 10.1086/520588

PMC ID: 7109895

PubMed ID: 17940968

SO-VID: a5c6c896-c524-4907-b440-6ec0c976a326

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This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections.

Sequence-Based Human Leukocyte Antigen—B Typing of Patients Infected with Ebola Virus in Uganda in 2000: Identification of Alleles Associated with Fatal and Nonfatal Disease Outcomes

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Most cited references 41

HLA B*5701 is highly associated with restriction of virus replication in a subgroup of HIV-infected long term nonprogressors.

Scheme for ranking potential HLA-A2 binding peptides based on independent binding of individual peptide side-chains.

Association of HLA class I with severe acute respiratory syndrome coronavirus infection

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