KIR3DL1 alleles and their epistatic interactions with human leukocyte antigen class I influence resistance and susceptibility to HIV-1 acquisition in the Pumwani sex worker cohort.

OBJECTIVE: To determine the associations of KIR3DL1/S1(3DL1/S1) and its epistatic interactions with human leukocyte antigen class I (HLA-I) alleles with resistance and susceptibility to HIV-1. DESIGN: Despite repeated exposure to HIV-1, a subset of women enrolled in the Pumwani sex worker cohort remain HIV uninfected. Previous studies have shown that specific HLA class I and II alleles were associated with this natural immunity. In this study, we investigated the association of 3DL1/S1 and its epistatic interactions with HLA-I, with resistance or susceptibility to HIV-1 acquisition. METHODS: We used a sequence-based typing method to genotype 3DL1/S1 of 641 women in this cohort. The association of 3DL1/S1 and its epistatic interactions with HLA-I were analyzed using SPSS statistics software. RESULTS: 3DL1041 is enriched in the HIV-1-resistant women [P = 0.009, Pc = 0.0468, odds ratio (OR): 3.359, 95% confidence interval (CI): 1.39-8.32], whereas, 3DL1020 was associated with susceptibility to HIV-1 infection before correction for multiple comparisons (P = 0.029, Pc = 0.0858, OR: 0.316, 95%CI: 0.10-1.04). Epistatic interactions between several 3DL1 alleles and specific HLA-I alleles were observed. Among them the cocarriage of 3DL1041 with Bw4 (P = 1E - 05, Pc = 0.0015, OR: 13.33, 95%CI: 3.43-51.9), or Bw6 (P = 0.008, Pc = 0.272, OR: 3.92, 95%CI: 1.51-10.17), increased the odds of remaining HIV-1 uninfected. Further, 3DL1041+/Bw4+ women who entered the cohort HIV negative remained uninfected (P = 0.032, Pc = 0.0858). Cocarriage of 3DL101501 with C02 : 10 (P = 2.73E - 07, Pc = 7.0954E - 06), B15 : 03 (P = 3.21E - 04, Pc = 0.0042), A24 supertype (P = 8.89E - 04, Pc = 0.0077), or A23 : 01 (P = 0.0036, Pc = 0.0236) was associated with increased susceptibility to seroconversion. CONCLUSION: The effects of interactions between 3DL1 and HLA-I alleles on resistance/susceptibility to HIV-1 infection suggest that innate immunity plays an important role in HIV-1 acquisition and should be studied and explored for HIV prevention.

Mauritian cynomolgus macaques with M3M4 MHC genotype control SIVmac251 infection.

BACKGROUND: Understanding natural HIV control may lead to new preventative or therapeutic strategies. Several protective major histocompatibility complex (MHC) genotypes were found in humans and rhesus macaques. Here, we report a simian immunodeficiency virus (SIV) controller MHC genotype in Mauritian cynomolgus macaques (MCMs). METHODS: Twelve MHC-genotyped MCMs were infected with SIVmac251 and monitored for viral loads and CD4+ T-cell counts. RESULTS: Two macaques with M3M4 genotype exhibited the lowest peak viral loads (log plasma SIV RNA copies/mL), nearly 3 logs lower than those in most macaques with other MHC haplotype combinations, and set point viral loads below the level of detection limit by RT-qPCR (<2 log RNA copies/mL). They maintained healthy CD4+ T-cell counts of >500 cells/µL blood, while CD4 counts in the vast majority of other macaques were below this level. CONCLUSIONS: The M3M4 MHC genotype may confer enhanced control of SIV replication in MCMs.

HLA-G and mother-child perinatal HIV transmission.

Transplacental passage is a well-known phenomenon in HIV infection and immune responses at the maternal-fetal interface play a critical role in perinatal mother-to-child HIV transmission (MCHT). The high expression of HLA-G at the maternal-fetal interface and its role in mediating immune tolerance suggest that it could play an important role in MCHT. We investigated the role of HLA-G polymorphism in perinatal HIV transmission in 348 ART naïve mother-child pairs enrolled in a mother-child HIV transmission cohort, established in Nairobi, Kenya in 1986. Among the 348 children born to 266 HIV+ mothers, 258 were uninfected and 90 became infected perinatally. HLA-G exons 2 and 3 of 266 mothers and 251 children were sequenced and genotyped. Among 14 HLA-G alleles identified, only 4 alleles have a phenotype frequency above 10%. Correlation analysis showed that HLA-G(∗)01:03+ mothers were less likely to perinatally transmit HIV-1 to their children (p=0.038, Odds ratio:0.472, 95%CI:0.229-0.973). Mother-child HLA-G concordance was not associated with the increased perinatal HIV transmission. There was no significant difference in the general health between the transmitting mothers and the mothers who did not transmit HIV to their children.

Characterization of HIV-specific CD4+ T cell responses against peptides selected with broad population and pathogen coverage.

CD4+ T cells orchestrate immunity against viral infections, but their importance in HIV infection remains controversial. Nevertheless, comprehensive studies have associated increase in breadth and functional characteristics of HIV-specific CD4+ T cells with decreased viral load. A major challenge for the identification of HIV-specific CD4+ T cells targeting broadly reactive epitopes in populations with diverse ethnic background stems from the vast genomic variation of HIV and the diversity of the host cellular immune system. Here, we describe a novel epitope selection strategy, PopCover, that aims to resolve this challenge, and identify a set of potential HLA class II-restricted HIV epitopes that in concert will provide optimal viral and host coverage. Using this selection strategy, we identified 64 putative epitopes (peptides) located in the Gag, Nef, Env, Pol and Tat protein regions of HIV. In total, 73% of the predicted peptides were found to induce HIV-specific CD4+ T cell responses. The Gag and Nef peptides induced most responses. The vast majority of the peptides (93%) had predicted restriction to the patient's HLA alleles. Interestingly, the viral load in viremic patients was inversely correlated to the number of targeted Gag peptides. In addition, the predicted Gag peptides were found to induce broader polyfunctional CD4+ T cell responses compared to the commonly used Gag-p55 peptide pool. These results demonstrate the power of the PopCover method for the identification of broadly recognized HLA class II-restricted epitopes. All together, selection strategies, such as PopCover, might with success be used for the evaluation of antigen-specific CD4+ T cell responses and design of future vaccines.

Identification of HLA-G*01:17, a new allele possibly generated by an interloci gene conversion event involving exon 3 of HLA-B.

HLA-G*01:17 was discovered in a woman of Kenyan descent who was enrolled in a mother-to-child HIV-1 transmission cohort. The new allele was identical to HLA-G*01:06 at exons 2, 3, and 4 with the exception of a base pair substitution at codon 169 (CAC → CGC) resulting in a coding change from histidine to arginine and codon 171 (TAC → CAC), resulting in turn in a coding change from tyrosine to histidine. The World Health Organization (WHO) Nomenclature Committee has named this allele HLA-G*01:17.

Enrichment of variations in KIR3DL1/S1 and KIR2DL2/L3 among H1N1/09 ICU patients: an exploratory study.

BACKGROUND: Infection by the pandemic influenza A (H1N1/09) virus resulted in significant pathology among specific ethnic groups worldwide. Natural Killer (NK) cells are important in early innate immune responses to viral infections. Activation of NK cells, in part, depend on killer-cell immunoglobulin-like receptors (KIR) and HLA class I ligand interactions. To study factors involved in NK cell dysfunction in overactive immune responses to H1N1 infection, KIR3DL1/S1 and KIR2DL2/L3 allotypes and cognate HLA ligands of H1N1/09 intensive-care unit (ICU) patients were determined. METHODOLOGY AND FINDINGS: KIR3DL1/S1, KIR2DL2/L3, and HLA -B and -C of 51 H1N1/09 ICU patients and 105 H1N1-negative subjects (St. Theresa Point, Manitoba) were characterized. We detected an increase of 3DL1 ligand-negative pairs (3DL1/S1(+) Bw6(+) Bw4(-)), and a lack of 2DL1 HLA-C2 ligands, among ICU patients. They were also significantly enriched for 2DL2/L3 ligand-positive pairs (P<0.001, Pc<0.001; Odds Ratio:6.3158, CI95%:2.481-16.078). Relative to St. Theresa aboriginals (STh) and Venezuelan Amerindians (VA), allotypes enriched among aboriginal ICU patients (Ab) were: 2DL3 (Ab>VA, P=0.024, Pc=0.047; Odds Ratio:2.563, CI95%:1.109-5.923), 3DL1*00101 (Ab>VA, P<0.001, Pc<0.001), 3DL1*01502 (Ab>STh, P=0.034, Pc=0.268), and 3DL1*029 (Ab>STh, P=0.039, Pc=0.301). Aboriginal patients ligand-positive for 3DL1/S1 and 2DL1 had the lowest probabilities of death (R(d)) (R(d)=28%), compared to patients that were 3DL1/S1 ligand-negative (R(d)=52%) or carried 3DL1*029 (R(d)=52%). Relative to Caucasoids (CA), two allotypes were enriched among non-aboriginal ICU patients (NAb): 3DL1*00401 (NAb>CA, P<0.001, Pc<0.001) and 3DL1*01502 (CA

Identification of four novel KIR2DL2 alleles and two novel KIR2DL3 alleles in an East African population.

We report four novel KIR2DL2 alleles and two novel KIR2DL3 alleles identified from an East African population using sequence-based typing. Sequencing and molecular cloning of exon 4 confirmed that the new 2DL2 alleles were identical to 2DL2*003, except for the following nucleotide differences: 2DL2*00601 had a difference at codon 16 (CGC→CCC), resulting in a coding change from arginine to proline; 2DL2*00602 also had this difference at codon 16, as well as a synonymous difference (GAT→GAC) at codon 31; 2DL2*00303 had a synonymous difference (AAA→AAG) at codon 61; and 2DL2*00304 had a synonymous difference (GGG→GGA) at codon 75. 2DL3*017 was identical to 2DL3*005 except at codon 11 (CGG→CTG, arginine→leucine) and exon 9, codons 297 (CAC→CGC, histidine→arginine) and 321 (TGA→AGA, stop codon→arginine). 2DL3*00104 was identical to KIR2DL3*001 except for a synonymous difference (GAG→GAA) at codon 54. Identification of novel killer cell immunoglobulin-like receptor (KIR) alleles is a testament to the genetic diversity in this population.

Identification of HLA-DPA1*020107 in an individual of Ugandan descent.

DPA1*020107 was identified from a woman of Ugandan origin by a taxonomy-based sequence analysis of human leukocyte antigen DPA1. The new allele was confirmed by cloning and sequencing of the polymerase chain reaction products. It is identical to DPA1*020101 with the exception of a single nucleotide synonymous substitution at codon 58 (GGC-->GGT). The World Health Organization Nomenclature Committee has named the allele as DPA1*020107.