Identification of a novel HLA-B*18 allele, B*18:119, using sequence-based typing in a caucasoid individual.

HLA-B*18:119 differs from HLA-B*18:01:01 at nucleotide 28 C>T in exon 4 changing histidine to tyrosine.

Full-length sequences of 3 HLA-B alleles, B*07:05:01:01, B*14:01:01 and B*18:02, confirmed by cloning and sequencing.

Full-length sequences of HLA-B*07:05:01:01, B*14:01:01 and B*18:02, confirmed by cloning and sequencing in Chinese donors.

Identification of 3 novel HLA-B alleles: B*08:173, B*18:72:03 and B*53:05:02.

A total of 3 novel human leukocyte antigen-B (HLA-B) alleles were detected by next generation sequencing and confirmed by monoallelic sequencing.

Characterization of a novel HLA-B*18 variant allele, HLA-B*18:122, by genome sequencing.

The HLA-B*18:122 allele showed four nucleotide differences from HLA-B*18:01:01:01.

Four new HLA class I alleles in Spaniards, HLA-A*32:01:23, HLA-B*18:01:24, HLA-B*18:72:02 and HLA-C*12:166.

Characterization of four new human leukocyte antigen (HLA) class I alleles, A*32:01:23, B*18:01:24, B*18:72:02 and C*12:166.

Exploring the Role of Killer Cell Immunoglobulin-Like Receptors and Their HLA Class I Ligands in Autoimmune Hepatitis.

BACKGROUND: Natural killer cells are involved in the complex mechanisms underlying autoimmune diseases but few studies have investigated their role in autoimmune hepatitis. Killer immunoglobulin-like receptors are key regulators of natural killer cell-mediated immune responses. METHODS AND FINDINGS: KIR gene frequencies, KIR haplotypes, KIR ligands and combinations of KIRs and their HLA Class I ligands were investigated in 114 patients diagnosed with type 1 autoimmune hepatitis and compared with a group of 221 healthy controls. HLA Class I and Class II antigen frequencies were compared to those of 551 healthy unrelated families representative of the Sardinian population. In our cohort, type 1 autoimmune hepatitis was strongly associated with the HLA-B18, Cw5, DR3 haplotype. The KIR2DS1 activating KIR gene and the high affinity HLA-C2 ligands were significantly higher in patients compared to controls. Patients also had a reduced frequency of HLA-Bw4 ligands for KIR3DL1 and HLA-C1 ligands for KIR2DL3. Age at onset was significantly associated with the KIR2DS1 activating gene but not with HLA-C1 or HLA-C2 ligand groups. CONCLUSIONS: The activating KIR gene KIR2DS1 resulted to have an important predictive potential for early onset of type 1 autoimmune hepatitis. Additionally, the low frequency of the KIR-ligand combinations KIR3DL1/HLA-Bw4 and KIR2DL3/HLA-C1 coupled to the high frequency of the HLA-C2 high affinity ligands for KIR2DS1 could contribute to unwanted NK cell autoreactivity in AIH-1.

Human leukocyte antigen B distribution in HIV discordant cohort from India.

Limited reports are available on association of HLA-B with HIV infection from India, a home to the third largest population of HIV infected people in the world. This emphasizes the need to have more information specifically the genetic constitution of HIV serodiscordant couples (DCs), where one spouse is seropositive (HSP) while the other remains seronegative (HSN) even after repeated exposure. Hence, aim of this study was to document association of HLA-B with HIV infection in DCs living in Mumbai, India. A cohort was designed to enroll DCs attending the ICTC/Shakti Clinic of KEM Hospital, Mumbai. A group of unexposed volunteers were also enrolled as healthy controls (HC). HLA-B alleles were typed using sequence-specific oligonucleotide probes. Allele frequency comparison was done using 2×2 contingency tables. Results were considered significant, when p<0.05 with two-tailed Fisher's exact test. At HLA-B locus, the frequencies of HLA-B*40;-B*35;-B*07;-B*15;-B*51;-B*44;-B*52;-B*37 and -B*57 were found in decreasing order in the population. Frequency of HLA-B*35 allele was significantly higher (HSP vs HSN; p<0.02 and HSP vs HC; p<0.04) in HSP. HLA-B*40 (HSN vs HSP; p<0.01 and HC vs HSP; p<0.01) and HLA-B*18 (HSN vs HSP; p<0.02) were significantly associated with HSN. Both HSN and HC had similar HLA-B*35 and -B*40 allele frequency. HLA-B*57 allele was observed in 15 individuals (3.69%). However, HLA-B*57:01 which is known to be associated with adverse reactions against Abacavir was observed in 7 of them. HLA-B*39 was observed exclusively in HSP. Our observation in DCs confirmed the association of HLA-B*35 with susceptibility while HLA-B*40 (specifically *B40:06), -B*18 with protection. These identified alleles can be used as possible marker associated with HIV transmission. In India, HLA screening is not carried out before initiation of HIV treatment. However, the presence of HLA-B*57:01 in the population emphasizes the importance of such screening to predict/avoid Abacavir hypersensitivity.

HLA peptide length preferences control CD8+ T cell responses.

Class I HLAs generally present peptides of 8-10 aa in length, although it is unclear whether peptide length preferences are affected by HLA polymorphism. In this study, we investigated the CD8(+) T cell response to the BZLF1 Ag of EBV, which includes overlapping sequences of different size that nevertheless conform to the binding motif of the large and abundant HLA-B*44 supertype. Whereas HLA-B*18:01(+) individuals responded strongly and exclusively to the octamer peptide (173)SELEIKRY(180), HLA-B*44:03(+) individuals responded to the atypically large dodecamer peptide (169)EECDSELEIKRY(180), which encompasses the octamer peptide. Moreover, the octamer peptide bound more stably to HLA-B*18:01 than did the dodecamer peptide, whereas, conversely, HLA-B*44:03 bound only the longer peptide. Furthermore, crystal structures of these viral peptide-HLA complexes showed that the Ag-binding cleft of HLA-B*18:01 was more ideally suited to bind shorter peptides, whereas HLA-B*44:03 exhibited characteristics that favored the presentation of longer peptides. Mass spectrometric identification of > 1000 naturally presented ligands revealed that HLA-B*18:01 was more biased toward presenting shorter peptides than was HLA-B*44:03. Collectively, these data highlight a mechanism through which polymorphism within an HLA class I supertype can diversify determinant selection and immune responses by varying peptide length preferences.

Naturally selected rilpivirine-resistant HIV-1 variants by host cellular immunity.

BACKGROUND: Rilpivirine is listed as an alternative key drug in current antiretroviral therapy (ART) guidelines. E138G/A/K in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) are rilpivirine resistance-associated mutations and can be identified in a few ART-naive patients, although at low frequency. The 138th position in HIV-1 RT is located in one of the putative epitopes of human leukocyte antigen (HLA)-B*18-restricted cytotoxic T lymphocytes (CTLs). CTL-mediated immune pressure selects escape mutations within the CTL epitope. Here we tested whether E138G/A/K could be selected by HLA-B*18-restricted CTLs. METHODS: The amino acid variation at the 138th position was compared between ART-naive HIV-1-infected patients with and without HLA-B*18. The optimal epitope containing the 138th position was determined and the impact of E138G/A/K on CTL response was analyzed by epitope-specific CTLs. The effect of E138G/A/K on drug susceptibility was determined by constructing recombinant HIV-1 variants. RESULTS: The prevalence of E138G/A/K was 21% and 0.37% in 19 and 1088 patients with and without HLA-B*18, respectively (odds ratio, 72.3; P = 4.9 × 10(-25)). The CTL response was completely abolished by the substitution of E138G/A/K in the epitope peptide. E138G/A/K conferred 5.1-, 7.1-, and 2.7-fold resistance to rilpivirine, respectively. CONCLUSIONS: E138G/A/K can be selected by HLA-B*18-restricted CTLs and confer significant rilpivirine resistance. We recommend drug resistance testing before the introduction of rilpivirine-based ART in HLA-B*18-positive patients.

A novel HLA-B18 restricted CD8+ T cell epitope is efficiently cross-presented by dendritic cells from soluble tumor antigen.

NY-ESO-1 has been a major target of many immunotherapy trials because it is expressed by various cancers and is highly immunogenic. In this study, we have identified a novel HLA-B*1801-restricted CD8(+) T cell epitope, NY-ESO-1(88-96) (LEFYLAMPF) and compared its direct- and cross-presentation to that of the reported NY-ESO-1(157-165) epitope restricted to HLA-A*0201. Although both epitopes were readily cross-presented by DCs exposed to various forms of full-length NY-ESO-1 antigen, remarkably NY-ESO-1(88-96) is much more efficiently cross-presented from the soluble form, than NY-ESO-1(157-165). On the other hand, NY-ESO-1(157-165) is efficiently presented by NY-ESO-1-expressing tumor cells and its presentation was not enhanced by IFN-γ treatment, which induced immunoproteasome as demonstrated by Western blots and functionally a decreased presentation of Melan A(26-35); whereas NY-ESO-1(88-96) was very inefficiently presented by the same tumor cell lines, except for one that expressed high level of immunoproteasome. It was only presented when the tumor cells were first IFN-γ treated, followed by infection with recombinant vaccinia virus encoding NY-ESO-1, which dramatically increased NY-ESO-1 expression. These data indicate that the presentation of NY-ESO-1(88-96) is immunoproteasome dependent. Furthermore, a survey was conducted on multiple samples collected from HLA-B18(+) melanoma patients. Surprisingly, all the detectable responses to NY-ESO-1(88-96) from patients, including those who received NY-ESO-1 ISCOMATRIX™ vaccine were induced spontaneously. Taken together, these results imply that some epitopes can be inefficiently presented by tumor cells although the corresponding CD8(+) T cell responses are efficiently primed in vivo by DCs cross-presenting these epitopes. The potential implications for cancer vaccine strategies are further discussed.