Perinatal transmission of human immunodeficiency virus (HIV) is a complex event that depends upon genetic and environmental factors. HIV vertical transmission has been associated with a variety of environmental, behavioral, viral, and genetic factors [1–5].
Within the genetic factors, polymorphisms of several genes, including these encoding chemokine receptors and their ligands, molecules of the innate and adaptive immunity such as MBL, defensins, and others such as the Fc receptor IIa for IgG, have been proposed as candidates for susceptibility to HIV perinatal transmission [6–15]. In addition, polymorphisms of human leukocyte antigens (HLAs) localized in both major histocompatibility complex (MHC) class I and II genes have been correlated to the predisposition to HIV infection in children and infants [16–20]. Various studies indicated functional HLA-G polymorphisms as involved in the risk of HIV infection [21,22] and in mother-to-child transmission [23–25].
HLA-G, a nonclassic MHC I gene primarily expressed at the level of extravillous cytotrophoblast cells, is localized at the maternal–fetal interface [26,27]. HLA-G can be considered as an important mediator of maternal–fetal tolerance due to its capability to protect the trophoblast and the fetus against maternal natural killer (NK) cells lysis [28,29]. HLA-G also inhibits maternal cytotoxic T lymphocytes thus contributing to immunological tolerance toward the fetus [30,31].
As HLA-G is expressed at the level of the maternal–fetal interface and is strongly involved in the regulation of the maternal–fetal immunity, a possible role of this molecule in the HIV mother-to-child transmission has been hypothesized.
Recently, Aikhionbare et al. [23,24] described, in two independent studies, an association between the concordance/discordance of HLA-G nucleotide variants in mothers and children pairs and risk of HIV-1 transmission.
Alternative splicing of HLA-G generates four membrane-bound (HLA-G1 to HLA-G4) and three soluble forms (HLA-G5 to HLA-G7) of this molecule [32,33]. An HLA-G allele, presenting a 14-bp insertion localized in the 3′ untranslated region (3′UTR), has been associated with a lower mRNA production, which may affect HLA-G function, for most membrane-bound and soluble isoforms in trophoblast samples [34,35]. Therefore, it can be hypothesized that different patterns of HLA-G expression may influence the local immune response involved both in the tolerance of the semiallogenic fetus [reviewed in ] and in protection against infection by intrauterine pathogens, including HIV.
We analyzed the 14-bp deletion/insertion polymorphism in two groups of Brazilian children born from HIV-positive mothers. One group included children that contracted HIV infection, whereas a second group included children who did not contract HIV despite perinatal exposure. We also studied HLA-G polymorphisms in a third group of healthy controls. The aim of our study was the identification of a possible association between the HLA-G 14-bp deletion/insertion polymorphism and perinatal virus transmission.
Patients and methods
We analyzed the DNA of 175 HIV-1 perinatally infected children (HIV+, 86 boys/89 girls, mean age 6.6 ± 4.4 years) and 71 exposed uninfected children (HIV−, 34 boys/37 girls, mean age 5.8 ± 3.7 years) collected prior to 1999 at the immunological day hospital of the Instituto Materno Infantil Prof. Fernando Figueira (IMIP) of Recife (Brazil). All children were born to HIV-1-positive mothers who did not receive antiretroviral therapy during pregnancy and were not subjected to caesarean section to prevent vertical HIV-1 transmission. A third group of 175 uninfected children (healthy controls, 87 boys/88 girls, mean age 7.1 ± 4.8 years), age-matched, sex-matched, and ethnic background-matched with the HIV-exposed groups but with no known risk or exposure to HIV infection, were enrolled as controls after obtaining informed consent by their parents.
Genomic DNA was extracted from peripheral whole blood by using the Wizard Genomic Purification kit (Promega, Madison, Wisconsin, USA) following manufacturer's indications.
HLA-G 14-bp deletion/insertion polymorphism (rs16375) was detected by polymerase chain reaction (PCR) amplification following the protocol of Lin et al. . The HLA-G 14-bp deletion/insertion polymorphism was detected by electrophoresis on 3% agarose gel: deleted and inserted allele generated a 210-bp and a 224-bp PCR fragment, respectively. PCR amplification results were confirmed by direct sequencing.
Allele and genotype frequencies were calculated by direct gene counting. Statistical significance of differences in allele and genotype frequencies was calculated by χ2 test using 2 × 2 (DF = 1) and 3 × 2 (DF = 2) contingency tables. Bonferroni's correction for multiple tests was performed; thus, only P values less than 0.003 were considered to be significant. All the statistical analyses were carried out by using free software open Epi (http://www.openepi.com, version 2.2.1). The odds ratio (OR) and 95% confidence interval (CI) were also computed.
We studied the frequency of the 14-bp deletion/insertion polymorphism in the 3′UTR of the HLA-G gene in Brazilian HIV-exposed infected children (HIV+), HIV-exposed uninfected children (HIV−), and healthy controls. All patients were genotyped by PCR and electrophoretic resolution of the amplicons; the results were confirmed by direct sequencing of the amplicons. Allele and genotype frequencies for the 14-bp deletion/insertion polymorphism in the three groups of individuals studied are shown in Table 1.
The allele and genotype frequencies were in Hardy–Weinberg equilibrium in healthy controls but not in the two groups of children exposed to HIV infection (Table 2).
We found significant differences in allele and genotype frequencies of the HLA-G 14-bp polymorphism in HIV-exposed uninfected children as compared with both HIV-exposed infected children and healthy controls.
The 14-bp-deleted (D) allele was more frequent in exposed uninfected children (79%) than in healthy controls (60%) and HIV-positive children (58%); the higher percentage of the D allele found in the exposed uninfected children as compared to HIV-positive individuals was significantly associated with a reduced risk of vertical transmission (P < 0.0001, OR 0.37, 95% CI 0.23–0.58).
In addition, genotypes frequencies were significantly different in HIV-exposed uninfected children as compared with exposed infected children (P < 0.0001) and unexposed uninfected (P < 0.0001) using 3 × 2 contingency tables. The homozygous D/D HLA-G genotype showed the highest frequency in HIV-exposed uninfected children (69% in HIV− vs. 38% in HIV+ and 34% in healthy controls) whereas the inserted (I) I/I genotype was most represented in HIV-exposed infected (HIV+ 23% vs. 11% in HIV− and 15% in healthy controls).
We did not detect any significant differences in allele and genotype frequencies between HIV-infected children and healthy controls.
To better understand the effect of the D allele on HIV transmission, we compared genotype distribution between HIV-positive and HIV-exposed uninfected children using a dominant and a recessive model. The dominant genetic model compares individual with one or two of the D allele (D/D and D/I patients) with the group carrying none of that allele (I/I patients). The recessive model compares the homozygous genotype (D/D) with the combined genotypes heterozygous and carrying none of that allele (D/I and I/I). By doing so, we observed that there was no association between the D allele and HIV infection in the dominant model (P > 0.05) whereas the effect of the D allele was consistent with a recessive genetic model (P < 0.0001, OR 0.28, 95% CI 0.15–0.50). Therefore, the protective effect of the D allele is exerted only when the polymorphism is present in homozygosis. The presence of a D/D genotype correlates with a reduced risk of infection in comparison with either the D/I genotype (P < 0.0001, OR 0.27, 95% CI 0.14–0.55) or the I/I genotype (P < 0.002, OR 0.28, 95% CI 0.12–0.65); the presence of the D/I genotype alone instead does not significantly reduce the risk of infection when compared to I/I (P > 0.8, OR≈1).
HLA-G is known to be expressed on the trophoblast at the level of maternal–fetal interface and is strongly involved in the regulation of maternal–fetal immune response. These and other features make HLA-G a good candidate for a role affecting HIV perinatal transmission. Moreover, an association between HLA-G genotype, HLA-G mRNA level, and protein expression, in particular, for a 14-bp deletion/insertion polymorphism in the 3′UTR of the gene, has been reported [38–40].
Two previous studies were performed to determine the allele frequency of the 14-bp deletion/insertion polymorphism in the Brazilian population, which represents one of the most ethnically heterogeneous populations in the world. Castelli et al.  found an insertion frequency in the HLA-G locus of about 44% in a population from Sao Paulo (an urban population sample, with a majority of European origin individuals). Mendes-Junior et al.  determined an insertion allele frequency of 38.54% in a population sample of Brazilian indigenous from the Central Amazon. We found an insertion frequency of the 40% in the children in our control population.
The Brazilian population from Recife is a homogeneous admixture of African, Caucasian, and native American populations estimated at 44, 34, and 22%, respectively . These ethnicities are reflected on the allelic frequencies of the HLA-G polymorphism studied in our healthy controls group, as they are intermediate between those reported on the NCBI genomic data bank for African and Caucasian populations (43 and 32% for the insertion allele, respectively).
We found significant differences in the frequencies of both the 14-bp insertion alleles and genotypes when we compared HIV-exposed uninfected children with HIV-exposed infected children and unexposed uninfected children. In particular, HIV-exposed infected and exposed uninfected children showed HLA-G 14-bp deletion/insertion polymorphism frequencies not in Hardy–Weinberg equilibrium; in both groups, the observed frequency of the heterozygote D/I genotype was lower than expected [0.39 vs. 0.49, χ2 = 6.4 (DF = 1), P = 0.012 in HIV+; 0.20 vs. 0.33, χ2 = 11.8 (DF = 1), P = 0.0006 in HIV−]. The deviation from Hardy–Weinberg equilibrium was probably due to the relatively small sample size of HIV-exposed uninfected individuals that we analyzed. In addition or in alternative, it is also possible that selection bias due to our restriction criteria (exposed infected or exposed uninfected) influenced the Hardy–Weinberg equilibrium in these two groups.
The D allele was significantly more frequent in exposed uninfected children than in HIV-positive children. The presence of the D allele was associated with a reduced risk of vertical transmission (P < 0.0001, OR 0.37, 95% CI 0.23–0.58). Moreover, we observed that the protective effect of the D allele is exerted only when the polymorphism is present in homozygosis. The presence of a D/D genotype correlates with a reduced risk of infection both confronted with the D/I genotype (OR 0.27) or the I/I genotype (OR 0.28) whereas the presence of the D/I genotype alone, instead, does not significantly reduce the risk of infection when compared to I/I.
Our finding that the frequencies of D/D genotypes in HIV-positive patients are comparable with those of the healthy controls can be explained by considering that the latter just represent the general population and the patients of this group have never been in contact with the HIV virus. One may assume that, if they were as well exposed to the virus, the D/D patients would have been at reduced risk of infection.
HLA-G functional polymorphisms have already been correlated with mother-to-child HIV-1 transmission in two independent studies performed on mother–child pairs by Aikhionbare et al. [23,24]: the authors showed that discordances in HLA-G genotypes between mothers and children are associated with HIV-1 vertical transmission. As biological samples from the mothers of the HIV-infected children were not available to us (and we also could not obtain information on maternal viral load at the time of delivery), we were unable to determine maternal HLA-G genotype. Consequently, our results cannot be compared with those of Aikhionbare et al., and no analysis of concordance could be performed. High viral loads are associated with an increased rate of vertical transmission, so it has to be considered that our findings could be biased by the absence of this information. Nevertheless, the very high difference of 14-bp deletion/insertion polymorphism genotype and allelic frequencies between HIV-exposed uninfected children and exposed infected children provides evidence in favor of a role of HLA-G in the susceptibility to mother-to-child HIV transmission.
In our study, we focused our attention on the HLA-G 14-bp deletion/insertion polymorphism because of its known influence on the mRNA stability. Alleles carrying the 14-bp inserted sequence have been associated with a lower mRNA production for most membrane-bound and soluble isoforms in trophoblast samples, and different alleles carrying this polymorphism have been shown to undergo alternative splicing events . An association between the presence of the 14-bp insertion allele in homozygosis, a very low mRNA expression of HLA-G3 isoform, and possibly an overall low HLA-G mRNA expression in placenta samples was also described . Furthermore, several studies have failed to detect soluble HLA-G in serum samples from individuals homozygous for the presence to the 14 insertion alleles [39,40].
Previous studies have shown that decreased HLA-G expression induces a T-helper type 1 (Th1) cytokine response, whereas high levels of HLA-G lead to a T-helper type 2 (Th2)-type cytokine response . The Th1 inflammatory response is characterized by elevated levels of cytokines such as tumor necrosis factor alpha (TNF-α) in maternal serum [45–47], and placental membrane inflammation has been associated with an increased risk of mother-to-child HIV-1 transmission .
A recent study also demonstrated that the villous trophoblast is susceptible to transcytosis of HIV-1 from infected peripheral blood mononuclear cells (PBMCs), and this process is enhanced by the Th1 cytokine TNF-α .
Thus, we hypothesize that the D allele, associated to an improved HLA-G expression, can contribute to create a Th2 local immune response, decreasing the production of pro-inflammatory cytokines, such as TNF-α, that can augment the risk of vertical transmission.
In conclusion, our findings, with the limitations mentioned above, support a possible role for the HLA-G 14-bp deletion/insertion polymorphism in the HIV vertical transmission in Brazilian children. In particular, presence of the D allele in homozygosis is protective toward perinatal HIV infection.
The authors thank Alfredo Garzino-Demo for critical revision of the manuscript. The study was supported by a grant from IRCCS Burlo Garofolo RC03/04; A.F. and L.S. are recipient of postdoctoral fellowships from IRCCS Burlo Garofolo. A.F. performed the DNA sequencing and HLA genotyping; E.C. provided technical support for DNA extraction and HLA genotyping; L.S. contributed to study design, data analysis, and statistics; M.M. performed the genotype–phenotype correlations; L.C.A. recruited the patients; J.L.D.L contributed to patients recruitment and statistical analysis; S.C. conceived the study design, redacted the manuscript, and contributed to genotype–phenotype correlations.
There was no conflict of interest.
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