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Introduction: We have reanalyzed the genomic data of the International Collaboration for the Genomics of HIV (ICGH), centering on HIV-1 Elite Controllers. Methods: We performed a genome-wide Association Study comparing 543 HIV Elite Controllers with 3,272 uninfected controls of European descent. Using the latest database for imputation, we analyzed 35,552 Single Nucleotide Polymorphisms (SNPs) within the Major Histocompatibility Complex (MHC) region. Results: Our analysis identified 2,626 SNPs significantly associated (p<5. 10-8) with elite control of HIV-1 infection, including well-established MHC signals such as the rs2395029-G allele which tags HLA-B*57:01. A thorough investigation of SNPs in linkage disequilibrium with rs2395029 revealed an extensive haploblock spanning 1.9 megabases in the MHC region tagging HLA-B*57:01, comprising 379 SNP alleles impacting 72 genes. This haploblock contains damaging variations in proteins like NOTCH4 and DXO and is also associated with a strong differential pattern of expression of multiple MHC genes such as HLA-B, MICB, and ZBTB12. The study was expanded to include two cohorts of seropositive African-American individuals, where a haploblock tagging the HLA-B*57:03 allele was similarly associated with control of viral load. The mRNA expression profile of this haploblock in African Americans closely mirrored that in the European cohort. Discussion: These findings suggest that additional molecular mechanisms beyond the conventional antigen-presenting role of class I HLA molecules may contribute to the observed influence of HLA-B*57:01/B*57:03 alleles on HIV-1 elite control. Overall, this study has uncovered a large haploblock associated with HLA-B*57 alleles, providing novel insights into their massive effect on HIV-1 elite control. [ABSTRACT FROM AUTHOR]

Background. To date, onlymutations in CCR5 have been shown to confer resistance to human immunodeficiency virus type 1 (HIV-1) infection, and these explain only a small fraction of the observed variability in HIV susceptibility. Methods. We performed a meta-analysis between 2 independent European genomewide association studies, each comparing HIV-1 seropositive cases with normal population controls known to be HIV uninfected, to identify single-nucleotide polymorphisms (SNPs) associated with the HIV-1 acquisition phenotype. SNPs exhibiting P < 10-5 in this first stage underwent second-stage analysis in 2 independent US cohorts of European descent. Results. After the first stage, a single highly significant association was revealed for the chromosome 8 rs6996198 with HIV-1 acquisition and was replicated in both second-stage cohorts. Across the 4 groups, the rs6996198-T allele was consistently associated with a significant reduced risk of HIV-1 infection, and the global meta-analysis reached genomewide significance: Pcombined = 7.76 × 10-8. Conclusions. We provide strong evidence of association for a common variant with HIV-1 acquisition in populations of European ancestry. This protective signal against HIV-1 infection is the first identified outside the CCR5 nexus. First clues point to a potential functional role for a nearby candidate gene, CYP7B1, but this locus warrants further investigation. [ABSTRACT FROM AUTHOR]

Background. Previous genomewide association studies (GWASs) of AIDS have targeted end points based on the control of viral load and disease nonprogression. The discovery of genetic factors that predispose individuals to rapid progression to AIDS should also reveal new insights into the molecular etiology of the pathology. Methods. We undertook a case-control GWAS of a unique cohort of 85 human immunodeficiency virus type 1 (HIV-1)-infected patients who experienced rapid disease progression, using Illumina HumanHap300 BeadChips. The case group was compared with a control group of 1352 individuals for the 291,119 autosomal single-nucleotide polymorphisms (SNPs) passing the quality control tests, using the false-discovery rate (FDR) statistical method for multitest correction. Results. Novel associations with rapid progression (FDR, ⩽25%) were identified for PRMT6 (P = 6.1 × 10-7; odds ratio [OR], 0.24), SOX5 (P = 1.8 × 106; OR, 0.45), RXRG (P = 3.9 × 10-6; OR, 3.29), and TGFBRAP1 (P = 7 × 10-6; OR, 0.34). The haplotype analysis identified exonic and promoter SNPs potentially important for PRMT6 and TGFBRAP1 function. Conclusions. The statistical and biological relevance of these associations and their high ORs underscore the power of extreme phenotypes for GWASs, even with a modest sample size. These genetic results emphasize the role of the transforming growth factor b pathway in the pathogenesis of HIV-1 disease. Finally, the wealth of information provided by this study should help unravel new diagnostic and therapeutic targets. [ABSTRACT FROM AUTHOR]

To elucidate the genetic factors predisposing to AIDS progression, we analyzed a unique cohort of 275 human immunodeficiency virus (HIV) type 1-seropositive nonprogressor patients in relation to a control group of 1352 seronegative individuals in a genomewide association study (GWAS). The strongest association was obtained for HCP5rs2395029 (P = 6.79 × 10-10; odds ratio, 3.47) and was possibly linked to an effect of sex. Interestingly, this single-nucleotide polymorphism (SNP) was in high linkage disequilibrium with HLA-B, MICB, TNF, and several other HLA locus SNPs and haplotypes. A meta-analysis of our genomic data combined with data from the previously conducted Euro-CHAVI (Center for HIV/AIDS Vaccine Immunology) GWAS confirmed the HCP5 signal (P = 3.02 × 10-19) and identified several new associations, all of them involving HLA genes: MICB, TNF, RDBP, BAT1-5, PSORS1C1, and HLA-C. Finally, stratification by HCP5 rs2395029 genotypes emphasized an independent role for ZNRD1, also in the HLA locus, and this finding was confirmed by experimental data. The present study, the first GWAS of HIV-1 nonprogressors, underscores the potential for some HLA genes to control disease progression soon after infection. [ABSTRACT FROM AUTHOR]

Interleukin (IL)—1 family members are key players in inflammatory processes but have been the subject of few studies of acquired immunodeficiency syndrome (AIDS). To better evaluate the impact of the IL-1 family on AIDS development, we genotyped the IL1α, IL1β, IL1Rα, and IL1R1 genes in 245 slow progressor (SP) and 82 rapid progressor (RP) human immunodeficiency virus type 1—seropositive patients as well as in 446 control subjects, all of whom were of white ethnicity. One hundred sixteen frequent polymorphisms were identified, of which 23 were newly characterized by our study. Many putative associations were found between single-nucleotide polymorphism (SNP) or haplotype alleles and the extreme profiles of progression. Most of them corresponded to weak associations (.01 < P < .05); however, the SNP IL1Ra_2134 exhibited a consistent association, found at the level of the SNP, haplotypes, and haploblocks, when the SP and control populations were compared (P = .0002). The IL-1-dependent inflammatory response is, thus, likely to play a role in AIDS progression via the regulation of IL-1Ra expression. This association will need to be confirmed in other AIDS cohorts, and experiments will also have to be performed to unravel the biological mechanisms at work. The data presented here will be useful for future genomic studies of the IL-1 family members in other infectious and chronic inflammatory diseases. [ABSTRACT FROM AUTHOR]

Abstract: Members of the secreted phospholipase A2 (PLA2) protein family can inhibit HIV-1 virus replication in vitro. To evaluate the impact of PLA2 gene polymorphisms on AIDS disease development, we studied 12 family members using SNPlex™ technology that permitted simultaneous typing of 70 tagging Single Nucleotide Polymorphisms (tagSNPs). The study utilized HIV-1 seropositive donors with slow progressor (n =168) or rapid progressor (n =54) status, plus 355 control subjects. All donors were Caucasian (total 577 individuals). Genetic associations yielded mainly 0.01< p <0.05, but lower p-values were obtained for four tagSNPs and seven haplotype alleles. These stronger associations corresponded to both secreted (PLA2G2A, PLA2G2D and PLA2G3) and cytosolic (PLA2G4A and PLA2G6) PLA2 genes, including three (PLA2G2A, PLA2G2D and PLA2G4A) implicated in the pathogenesis of other diseases. Our results suggest that the PLA2 gene family may represent genes of interest for a larger study targeting all the known tagSNPs in the PLA2 genes. The data presented in this study will have to be confirmed in other AIDS cohorts and will also be useful for studies undertaken on the PLA2 gene family in other disease cohorts. [Copyright &y& Elsevier]