Abstract
Certain host genetic variants, especially in the human leucocyte antigen (HLA) region, are associated with different progression of HIV-1-induced diseases and AIDS. Long term non progressors (LTNP) represent only the 2% of infected patients but are especially relevant because of their efficient HIV control. In this work we present a global analysis of genetic data in the large national multicenter cohort of Spanish LTNP, which is compared with seronegative individuals and HIV-positive patients. We have analyzed whether several single-nucleotide polymorphisms (SNPs) including in key genes and certain HLA-A and B alleles could be associated with a specific HIV phenotype. A total of 846 individuals, 398 HIV-1-positive patients (213 typical progressors, 55 AIDS patients, and 130 LTNPs) and 448 HIV-negative controls, were genotyped for 15 polymorphisms and HLA-A and B alleles. Significant differences in the allele frequencies among the studied populations identified 16 LTNP-associated genetic factors, 5 of which were defined for the first time as related to LTNP phenotype: the protective effect of HLA-B39, and the detrimental impact of HLA-B18, -A24, -B08 and –A29. The remaining eleven polymorphisms confirmed previous publications, including the protective alleles HLA-B57, rs2395029 (HCP5), HLA bw4 homozygosity, HLA-B52, HLA-B27, CCR2 V64I, rs9264942 (HLA-C) and HLA-A03; and the risk allele HLA bw6 homozygosity. Notably, individual Spanish HIV-negative individuals had an average of 0.12 protective HLA alleles and SNPs, compared with an average of 1.43 protective alleles per LTNP patient, strongly suggesting positive selection of LTNP. Finally, stratification of LTNP according to viral load showed a proportional relationship between the frequency of protective alleles with control of viral load. Interestingly, no differences in the frequency of protection/risk polymorphisms were found between elite controllers and LTNPs maintaining viral loads <2.000 copies/mL throughout the follow-up.
Highlights
The host genetic determinants influencing progression of HIV infection to disease and acquired immunodeficiency syndrome (AIDS) have been extensively studied in several cohorts of Long term non progressors (LTNP) individuals of Caucasian ancestry
Regarding the Δ32 deletion of the CCR5 HIV-1 co-receptor locus that is associated with delayed HIV disease progression [1, 2, 5], a higher frequency of the protective WT/Δ32 genotype was observed in LTNP than in the AIDS group, but these differences did not reach statistical significance after false discovery rate (FDR) correction
The present study aims to investigate the role of genetic factors in a large (n = 130) Spanish cohort of LTNP
Summary
The host genetic determinants influencing progression of HIV infection to disease and acquired immunodeficiency syndrome (AIDS) have been extensively studied in several cohorts of LTNP individuals of Caucasian ancestry. This is the case of several allelic variants in genes encoding the HIV-1 co-receptors and their ligands, such as CCR2 and CCR5, certain cytokines such as IL10, co-factors and interferon-induced proteins [1,2,3,4,5,6,7,8,9]. Studies based on genome-wide association strategies identified novel genetic variants associated with delayed disease progression [18,19,20,21,22,23,24,25], most of them within the HLA complex [19, 23, 24]
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