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      SNP screening of central MHC identified HLA-DMB as a candidate susceptibility gene for HIV-related Kaposi’s sarcoma

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          The major histocompatibility complex (MHC) region on chromosome 6p21.3 is suspected to host susceptibility loci for HIV-related Kaposi’s sarcoma (HIV-KS). A nested case-control study in the Multicenter AIDS Cohort Study was designed to conduct fine genetic association mapping across central MHC. Individuals co-infected with HIV-1 and HHV-8 who later developed KS were defined as cases (n=354) and were matched 1:1 with co-infected KS-free controls.

          We report data for new independent MHC class II and III susceptibility loci. In particular, class II HLA-DMB emerged as a strong candidate, with the intronic variant rs6902982 A>G associated with a 4-fold increase of risk (OR= 4.09; 95% CI: 1.90–8.80; p= 0.0003). A striking multiplicative effect on the estimated risk was associated with further carriage of two non-synonymous variants, rs1800453 A>G (Asp697Gly) and rs4148880 A>G (Ile393Val), in the linked TAP1 gene (OR=10.5; 95% CI: 2.54–43.6; p=0.0012). The class III susceptibility variant is moderately associated with HIV-KS and lies within a 120 Kb-long haplotype (OR=1.52; 95% CI: 1.01–2.28; p=0.047) formed by rs7029 A>G ( GPANK1 3’UTR), rs1065356 G>A ( LY6G6C), rs3749953 A>G ( MSH5-SAPCD1 readthrough) and rs707926 G>A ( VARS). Our data suggest that antigen processing by MHC class II molecules is a target pathway in the pathogenesis of HIV-KS.

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          Most cited references 33

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          Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma.

          Representational difference analysis was used to isolate unique sequences present in more than 90 percent of Kaposi's sarcoma (KS) tissues obtained from patients with acquired immunodeficiency syndrome (AIDS). These sequences were not present in tissue DNA from non-AIDS patients, but were present in 15 percent of non-KS tissue DNA samples from AIDS patients. The sequences are homologous to, but distinct from, capsid and tegument protein genes of the Gammaherpesvirinae, herpesvirus saimiri and Epstein-Barr virus. These KS-associated herpesvirus-like (KSHV) sequences appear to define a new human herpesvirus.
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            The Multicenter AIDS Cohort Study: rationale, organization, and selected characteristics of the participants.

            The Multicenter AIDS Cohort Study was designed to elucidate the natural history of the infection causing acquired immunodeficiency syndrome (AIDS), identify risk factors for occurrence and clinical expression of the infection, and establish a repository of biologic specimens for future study. A variety of recruitment techniques, including special assurance of confidentiality, were used to enroll participants. Nearly 5,000 homosexual men volunteered for semiannual interview, physical examination, and laboratory testing in four metropolitan areas. A significant majority of these men in each center (69-83%) reported having 50 or more lifetime sexual partners, and over 80% had engaged in receptive anal intercourse with at least some of their partners in the previous two years. By the time of the participants' initial evaluation (April 1984-April 1985), infection with the human immunodeficiency virus (HIV) had occurred in higher proportions of men in Los Angeles (51%) and Chicago (43%) than in Baltimore/Washington, DC (31%) and Pittsburgh (21%), presumably as a result of the higher number of partners and proportion with whom these men had engaged in high-risk practices (e.g., receptive anal intercourse). Follow-up evaluations are underway in this comprehensive longitudinal investigation of HIV infection.
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              HLA-DM Captures Partially Empty HLA-DR Molecules for Catalyzed Peptide Removal

              The mechanisms of HLA-DM catalyzed peptide exchange remain uncertain. We found that all stages of the interaction of DM with HLA-DR were dependent on the occupancy state of the peptide binding groove. High-affinity peptides were protected from removal by DM through two mechanisms: peptide binding induced dissociation of a long-lived complex of empty DR and DM, and high-affinity DR-peptide complexes bound DM only very slowly. Non-binding covalent DR-peptide complexes were converted to efficient DM binders upon truncation of an N-terminal peptide segment that emptied the P1 pocket and disrupted conserved hydrogen bonds to MHC. DM thus only binds to DR conformers in which a critical part of the binding site is vacant, due to spontaneous peptide motion.

                Author and article information

                Genes Immun
                Genes Immun.
                Genes and immunity
                20 June 2014
                10 July 2014
                September 2014
                01 March 2015
                : 15
                : 6
                : 424-429
                [1 ]Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA
                [2 ]Department of Epidemiology, Johns Hopkins University, Baltimore, MD, USA
                [3 ]Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
                Author notes
                [# ]Address Correspondence to: Brahim Aissani, PhD, baissani@



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