Abstract
Post-transcriptional regulatory elements associated with transcript degradation or transcript instability have been described at the 3’ untranslated region (3’UTR) of the HLA-G gene. Considering that HPV infection and aneuploidy, which causes gene instability, are associated with cervical cell malignancy, as well as the fact that HIV infection and HLA-G may modulate the immune response, the present study aimed to compare the frequencies of HLA-G 3′UTR polymorphic sites (14-base pair insertion/deletion, +3142C/G, and +3187A/G) between 226 HIV+ women co-infected (n = 82) or not with HPV (n = 144) and 138 healthy women. We also evaluated the relationship between those HLA-G 3’UTR variants and aneuploidy in cervical cells. HPV types and HLA-G polymorphisms were determined by PCR and sequencing of cervical samples DNA. Aneuploidy in cervical cell was measured by flow cytometry. The HLA-G 3’UTR 14-bp ins/del was not associated with either HIV nor HIV/HPV co-infection. The +3142G allele (p = 0.049) and +3142GG genotype (p = 0.047) were overrepresented in all HIV-infected women. On the other hand, the +3187G allele (p = 0.028) and the +3187GG genotype (p = 0.026) predominated among healthy women. The +3142G (p = 0.023) and +3187A (p = 0.003) alleles were associated with predisposition to HIV infection, irrespective of the presence or not of HIV/HPV co-infection. The diplotype formed by the combination of the +3142CX (CC or CG) and +3187AA genotype conferred the highest risk for aneuploidy in cervical cell induced by HPV. The HLA-G 3’UTR +3142 and +3187 variants conferred distinct susceptibility to HIV infection and aneuploidy.
Highlights
The human leukocyte antigen-G (HLA-G) is a non-classical major histocompatibility complex molecule, characterized by low protein variability and restricted tissue distribution
We evaluated 226 women from a human immunodeficiency virus (HIV)-infected cohort that had been previously studied by our research group and had shown low frequency of high-grade cervical lesion and high adherence to antiretroviral therapy [27], which is provided at no cost to the patient by the Brazilian government
We believe that by including a screening step for selecting only HLA-G polymorphic sites that contribute to susceptibility to viral infection, we minimize the inclusion of genetic factors not related to it
Summary
The human leukocyte antigen-G (HLA-G) is a non-classical major histocompatibility complex molecule, characterized by low protein variability and restricted tissue distribution. HLA-G was initially identified in cytotrophoblast cells and plays an important role in the modulation of the immune response by inhibiting maternal NK and CD8+ T cytotoxic cells, and inducing IL-10 producing T regulatory cells at the maternal-fetal interface, which are crucial events for fetus survival [1,2]. HLA-G expression may be differentially modulated by variation sites especially those at the regulatory regions of the HLA-G gene (promoter and 3’ untranslated sequence) [5,6,7]. Three variation sites at the HLA-G 3’ untranslated region (3’UTR) are important for the post-transcriptional regulation of HLA-G: the 14-base pair (14-bp) insertion/deletion variants influence HLA-G mRNA stability [8,9], the +3142C/G variants regulate HLA-G expression mediated by specific microRNAs [10,11], and the +3187A/G variants affect HLA-G mRNA degradation [12]. Polymorphic sites observed at HLA-G 3’UTR have been associated with risk to develop cancer [13], autoimmunity disorders [14,15], and infectious diseases [11,16], among other conditions
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