HLA-G Alleles Impact the Perinatal Father-Child HPV Transmission.

The host factors that influence father-to-child human papillomavirus (HPV) transmission remain unknown. This study evaluated whether human leukocyte antigen (HLA)-G alleles are important in father-to-child HPV transmission during the perinatal period. Altogether, 134 father-newborn pairs from the Finnish Family HPV Study were included. Oral, semen and urethral samples from the fathers were collected before the delivery, and oral samples were collected from their offspring at delivery and postpartum on day 3 and during 1-, 2- and 6-month follow-up visits. HLA-G alleles were tested by direct sequencing. Unconditional logistic regression was used to determine the association of the father-child HLA-G allele and genotype concordance with the father-child HPV prevalence and concordance at birth and during follow-up. HLA-G allele G*01:01:03 concordance was associated with the father's urethral and child's oral high-risk (HR)-HPV concordance at birth (OR 17.00, 95% CI: 1.24-232.22). HLA-G allele G*01:04:01 concordance increased the father's oral and child's postpartum oral any- and HR-HPV concordance with an OR value of 7.50 (95% CI: 1.47-38.16) and OR value of 7.78 (95% CI: 1.38-43.85), respectively. There was no association between different HLA-G genotypes and HPV concordance among the father-child pairs at birth or postpartum. To conclude, the HLA-G allele concordance appears to impact the HPV transmission between the father and his offspring.

The association of HLA-G polymorphism with oral and genital HPV infection in men.

The host genetic factors that influence the natural history of human papillomavirus (HPV) infection in men are not well known. Our aim was to evaluate the role of human leukocyte antigen (HLA)-G polymorphism in oral and genital HPV infection in men. Altogether, 130 men from the Finnish Family HPV Study, with a 6-year follow-up, were included in the analyses. HLA-G alleles were tested by direct sequencing. Oral, urethral, and semen samples were collected and analyzed for 24 different HPV genotypes. Unconditional logistic regression was used to determine associations between HLA-G alleles and genotypes with HPV infection and its outcomes. Overall, eight different HLA-G alleles were identified with 15 different HLA-G genotype combinations. The most common HLA-G allele among the men was G*01:01:01 (86.2%, n = 112) followed by G*01:01:02 (36.2%, n = 47). Allele G*01:01:02 showed to be protective against any- and high-risk (HR) oral HPV (OR range of 0.20-0.24, 95% CI range of 0.06-0.85). Men having allele G*01:01:01 showed a reduced risk for incident (OR 0.30, 95% CI 0.11-0.84) and persistent (OR 0.24, 95% CI 0.08-0.69) oral infections. Allele G*01:01:03 was associated with increased risk for urethral HR-HPV infections (OR 4.94, 95% CI 1.34-18.27). Among self-reported demographic data, genotype G*01:01:01/01:01:03 was associated with an increased risk for oral warts (OR 8.00, 95% CI 1.23-51.89) and allele G*01:03:01 increased the risk of pollen and/or animal allergy (OR 13.59, 95% CI 1.57-117.25). To conclude, HLA-G polymorphism in men largely impacts the outcome of an oral HPV infection and seems to associate with self-reported allergies.

Natural Immunity to HIV is associated with Low BLyS/BAFF levels and low frequencies of innate marginal zone like CD1c+ B-cells in the genital tract.

BLyS/BAFF is recognized for its role in B-cell ontogenesis, as well as cell fate decision towards the first-line/innate marginal zone (MZ) B-cell pool. Excess BLyS/BAFF is associated with hyperglobulinemia and increased frequencies of activated precursor-like MZ B-cells. Herein, we show that HIV highly-exposed seronegative (HESN) commercial sex workers (CSWs) had lower soluble BLyS/BAFF levels and relative frequencies of BLyS/BAFF expressing cells in their genital mucosa when compared to those from HIV-infected CSWs and HIV-uninfected non-CSWs. Furthermore, we identified genital innate and/or marginal zone (MZ)-like CD1c+ B-cells that naturally bind to fully glycosylated gp120, which frequencies were lower in HESNs when compared to HIV-infected CSWs and HIV-uninfected non-CSWs. Although genital levels of total IgA were similar between groups, HESNs had lower levels of total IgG1 and IgG3. Interestingly, HIV-gp41 reactive IgG1 were found in some HESNs. Low genital levels of BLyS/BAFF observed in HESNs may allow for controlled first-line responses, contributing to natural immunity to HIV.

HLA-G polymorphism impacts the outcome of oral HPV infections in women.

BACKROUND: Human leukocyte antigen (HLA)-G may have an important role in the natural history of human papillomavirus (HPV) infection. Our aim was to evaluate the role of HLA-G in the outcome of genital and oral HPV infections in women. METHODS: Analyses included 306 women from the Finnish Family HPV-study and were followed-up for six years. Genital and oral samples were tested for 24 different HPV types with multiplex HPV genotyping. HLA-G alleles were determined through direct DNA-sequencing. Unconditional logistic regression was used to determine the associations between HLA-G genotypes and HPV infection outcomes. RESULTS: Ten HLA-G alleles were identified. Most common HLA-G genotypes were the wild type G*01:01:01/01:01:01 (31.3%) followed by G*01:01:01/01:01:02 (26.8%). G*01:01:01/01:01:01 genotype was associated with increased risk of oral HPV infections by any HPV type or single-type with OR = 1.86 (95% CI 1.14-3.04, P = 0.01) and 2.22 (95% CI 1.14-3.71, P = 0.02), respectively. G*04:01+ allele and the G*01:01:01/01:04:01 genotype both protected from any and single oral HPV infections; OR = 0.46 (95% CI 0.23-0.89, P = 0.02) and 0.53 (95% CI 0.23-0.97, P = 0.03), respectively. G*01:01:02/01:04:01 genotype increased significantly the risk of infertility and its treatments, with respective OR = 5.06 (95% CI 1.22-21.02, P = 0.03) and OR = 9.07 (95% CI 1.22-39.50, P = 0.03). Both HLA-G alleles and genotypes showed several significant associations with the outcomes of oral HPV infections, but none of them had any impact on the outcomes of genital HPV infections in these women. CONCLUSIONS: The host HLA-G genotypes appear to impact the outcomes of oral HPV infections in women but have little if any effect on genital HPV status or infection outcomes.

HLA-G and vertical mother-to-child transmission of human papillomavirus infection.

Role of host factors in transmission of human papillomavirus (HPV)-infection from mother to her offspring is not known. Our aim was to study whether human leukocyte antigen (HLA)-G allele concordance among the mother-child pairs could facilitate vertical transmission of HPV, because HLA-G may contribute to immune tolerance in pregnancy. Altogether, 310 mother-child pairs were included from the Finnish Family HPV study. Overall, nine different HLA-G alleles were identified. The HLA-G genotype concordance of G∗01:01:01/01:04:01 increased the risk of high risk (HR)-HPV genotype positivity in cord blood and infant's oral mucosa. The mother-child concordance of G∗01:01:02/01:01:02 increased the risk of oral HPV positivity with HR-HPV genotypes both in the mother and offspring; OR 2.45 (95%CI 1.24-4.85). Discordant HLA-G allele for G∗01:04:01 and for G∗01:06 was significantly associated with infant's oral low risk (LR)-HPV at birth, OR 3.07 (95%CI 1.01-9.36) and OR 5.19 (95%CI 1.22-22.03), respectively. HLA-G had no association with HPV genotype-specific concordance between the mother and child at birth nor influence on perinatal HPV status of the child. Taken together, our results show that HLA-G molecules have a role in predicting the newborn's likelihood for oral HPV infection at birth.

Human Leukocyte Antigen G Polymorphism and Expression Are Associated with an Increased Risk of Non-Small-Cell Lung Cancer and Advanced Disease Stage.

Human leukocyte antigen (HLA)-G acts as negative regulator of the immune responses and its expression may enable tumor cells to escape immunosurveillance. The purpose of this study was to investigate the influence of HLA-G allelic variants and serum soluble HLA-G (sHLA-G) levels on risk of non-small-cell lung cancer (NSCLC). We analyzed 191 Caucasian adults with NSCLC and 191 healthy subjects recruited between January 2009 and March 2014 in Ariana (Tunisia). Serum sHLA-G levels were measured by immunoassay and HLA-G alleles were determined using a direct DNA sequencing procedures. The heterozygous genotypes of HLA-G 010101 and -G 010401 were associated with increased risks of both NSCLC and advanced disease stages. In contrast, the heterozygous genotypes of HLA-G 0105N and -G 0106 were associated with decreased risks of NSCC and clinical disease stage IV, respectively. Serum sHLA-G levels were significantly higher in patients with NSCLC and particularly in those with advanced disease stages compared to healthy subjects. The area under the receiver-operating characteristic (ROC) curves was 0.82 for controls vs patients. Given 100% specificity, the highest sensitivity achieved to detect NSCLC was 52.8% at a cutoff value of 24.9 U/ml. Patients with the sHLA-G above median level (≥ 50 U/ml) had a significantly shorter survival time. This study demonstrates that HLA-G allelic variants are independent risk factors for NSCLC. Serum sHLA-G levels in NSCLC patients could be useful biomarkers for the diagnostic and prognosis of NSCLC.

New transporter associated with antigen processing (TAP-2) polymorphisms in the Shona people of Zimbabwe.

Most studies, to date, on transporter associated with antigen processing (TAP2) polymorphism have been conducted in Caucasians or Asians from industrialized countries. Because of the essential role of this molecule in antigen processing, the implication that polymorphism could be a major factor in human disease and the possible genetic variation at this locus among ethnically diverse populations, we undertook a study to analyze the full extent of TAP2 polymorphism in an indigenous Zimbabwean population (Shona ethnic group). Using single-stranded conformation polymorphism and DNA direct sequencing procedures, we detected the presence of 17 nucleotide sequence variations in the entire coding region of TAP2. Of these variants, 11 are nonconservative substitutions with respect to amino acid composition and are located in a region of the protein that could modulate its function. Six new polymorphic sites were identified in exon 1 (codons 15 Val-->Ala, 53 Leu-->Val), exon 3 (codon 220 Arg-->Arg), exon 4 (codons 257 Thr-->Ile, 313 Arg-->His), and exon10 (codon 609 Ala-->Val). Significant differences were seen in the distribution of the known 374Thr, 565Thr and 651Cys variants between African and non-African populations. These differences may reflect evolutionary pressures generated by environmental factors, such as prevalent pathogens in these geographically distinct regions. Further studies are needed to elucidate the net impact of TAP2 polymorphism on the protein's function and it's role in disease pathogenesis.

Novel TAP1 polymorphisms in indigenous Zimbabweans: their potential implications on TAP function and in human diseases.

Because of the essential role of transporter associated with antigen processing (TAP1 or TAP2) molecule in antigen processing, the implication of its polymorphism as a factor involved in human diseases and the possible genetic variation at this locus among ethnically diverse populations, we underwent a study to analyze the full extent of TAP1 polymorphism in an indigenous Zimbabwean population (Shona ethnic group). Using single-stranded conformation polymorphism and DNA direct sequencing procedures, we detected the presence of 11 nucleotide sequence variations in the entire coding region of TAP1. Of these variants, eight are nonconservative substitutions with respect to amino acid composition and are located in a critical part of the protein that could modulate its function. Five new polymorphic sites were identified in exon 1 (codons 7 Pro --> Ser, 17 Gly --> Arg, 141 Val --> Val), exon 6 (codon 419 Gly --> Cys), and exon 7 (codon 487 Arg --> Arg). Significant differences were seen in the distribution of TAP1*0201 and TAP1*0401 alleles, and codon 333 (Ile --> Val) polymorphism among African and non-African populations. Thus, TAP1 polymorphism has evolved differently among populations presumably because of the evolutionary pressures generated by prevalent pathogens in these geographically distinct regions.

The frequency of HLA alleles in a population of Inuit women of northern Quebec.

BACKGROUND: Human leukocyte antigen (HLA) alleles code for proteins that are involved in the recognition of foreign antigens and activation of the immune system. The frequency of HLA alleles varies across different populations. OBJECTIVE: To describe the frequency of HLA alleles in a population of Inuit women of Nunavik, Quebec, Canada. DESIGN: A cohort of women was recruited from 4 different communities between January 2002 and December 2007. HLA-B*07, HLA-DQB1*03, DQB1*06:02, DRB1*13 and DRB1*15:01 alleles were typed by PCR sequence-specific primers (PCR-SSP) and HLA-E and G alleles were type by DNA-sequencing procedures. RESULTS: We obtained data on 524 participants. The most frequent HLA alleles in this population were HLA-E*01:03, HLA-G*01:04:01 and HLA-DQB1*03, and they were found in 89, 75 and 94% of the population, respectively. CONCLUSIONS: The distribution of HLA alleles in Nunavik, Quebec is unique when compared to other populations in Canada or around the world.

The association between human leukocyte antigen (HLA)-G polymorphisms and human papillomavirus (HPV) infection in Inuit women of northern Quebec.

BACKGROUND: The human leukocyte antigen (HLA)-G molecules act as negative regulators of the immune response. We analyzed the associations between HLA G polymorphisms and human papillomavirus (HPV) infection and squamous intraepithelial lesions (SIL) in Inuit women from Nunavik, northern Quebec. METHODS: Cervical specimens from a cohort study of 548 Inuit women were tested for HPV DNA. HPV genotypes were classified according to tissue-tropism groupings of alpha-papillomavirus species: alpha group 1 includes low risk (LR) cervical species, group 2 includes high risk (HR) cervical species, and group 3 includes LR vaginal species. HLA-G alleles were typed using direct DNA sequencing. RESULTS: HLA-G(∗)01:01:01 was associated with an increased risk of period prevalent alpha groups 1 (OR = 2.23, 95% CI:1.08-4.59) and 3 (OR = 1.70, 95% CI:1.09-2.65). The homozygous HLA-G(∗)01:04:01 genotype was associated with a decreased risk of alpha group 3 infection period prevalence (OR = 1.69 95% CI = 1.07-2.67). No HLA-G alleles were significantly associated with HPV persistence. HLA-G(∗)01:01:02, G(∗)01:04:01 and G(∗)01:06 were associated with high grade (HG)SIL, but the association did not reach statistical significance. CONCLUSIONS: These results suggest that HLA-G polymorphisms play a role in the natural history of HPV infection, likely at the stage of host immune recognition. HLA-G polymorphisms interacted differently with the three alpha papillomavirus groups.