Polymorphisms in cytokine genes define subpopulations of HIV-1 patients who experienced immune restoration diseases

ArticleinAIDS 16(15):2043-7 · November 2002with5 Reads
DOI: 10.1097/00002030-200210180-00009 · Source: PubMed
Abstract
To further elucidate the immunopathogenesis of immune restoration diseases (IRD) in HIV patients responding to antiretroviral therapy and determine whether IRD associated with different opportunistic pathogens involve distinct immunopathological mechanisms. DNA samples from patients with a range of IRD were typed for polymorphic loci in genes encoding immune-mediators. PCR-restriction fragment length polymorphism assays were used to type loci in the and genes. Alleles of a microsatellite in the CD30 promoter were determined by capillary electrophoresis. Only 8% of patients with IRD associated with a herpesvirus infection carried IL12B-3'UTR*2, compared with 42-54% of patients with other or no IRD. Patients with IRD arising from mycobacterial infection rarely carried IL6-174*C (36% versus 61-71%) and never carried TNFA-308*2 (0% versus 23-52%). TNFA-308*2 was carried by 52% of patients who experienced IRD associated with a herpesvirus infection, as several patients with exacerbations of cytomegalovirus retinitis carried this as part of a HLA-A2,B44 haplotype. Polymorphisms in and showed no distinct patterns. Distinct cytokine-mediated mechanisms contribute to IRD initiated by herpesvirus and mycobacterial infections.
    • "The condition manifest with a wide range of clinical presentations and is associated with a number of antigenic targets [13,14] , including, for example, antigens from viable replicating infective pathogens during a sub-clinical infection (unmasking IRIS), or from dead pathogen debris and dying of non-infective pathogens (paradoxical IRIS), host antigen (autoimmune disease), tumor antigen and other inflammatory conditions131415. The pathogenesis of IRIS is poorly understood, however, monocytes and natural killer (NK) cells involved in innate immunity, inappropriate function of T-cell, polymorphism in human leukocyte antigen (HLA) and cytokine-related genes, have been associated with this clinical condition [16,17]. IL-23R is a type 1 trans-membrane protein found on dendritic cells, monocytes, activated T-cells and NK cells [18]. "
    [Show abstract] [Hide abstract] ABSTRACT: Background Human Immunodeficiency Virus (HIV) and Schistosomiasis co-infection is common among residents at the shores of Lake Victoria in Kenya. About 36% of this population initiating antiretroviral therapy (ART) experience Immune Reconstitution Inflammatory Syndrome (IRIS) that complicates recovery. Several IL-23R alleles have been associated with susceptibility to both autoimmune and inflammatory diseases through T-helper type 17 (TH17) cells. However, whether or not variants within the IL-23R increase susceptibility to IRIS in western Kenya is unknown. The objective of the current study was to determine the association between IL-23R gene polymorphisms, CD4+ cell counts and HIV RNA levels and IRIS in HIV and Schistosoma mansoni co-infected patients undergoing highly active anti-retroviral therapy (HAART). Methods A three-month case–control study was conducted on antiretroviral naïve schistosomiasis/HIV co-infected fishermen starting HAART in Uyoma Rarieda, Siaya County, Kenya. Seventy one patients were sampled at baseline and followed up for three months, to establish if they developed Schistosoma-related IRIS. In addition, the CD4+ cell counts and HIV RNA levels were determined in pre- and post-administration of HAART. Variations at five polymorphic sites of IL-23R (rs1884444, rs11465754, rs6682925, rs7530511 and rs7539625) based on >10% minor allele frequency in Yoruban reference population was determined using Allelic Discrimination Assay. The association between the five variants and susceptibility to IRIS was determined using logistic regression while controlling for potential confounders. In addition, the functional differences between the baseline CD4 + Cell counts and viral loads were determined using medians while across IL-23R genotypes were determined using Kruskal-Wallis tests. Results Overall, 26 (36.6%) patients developed schistosomiasis-associated IRIS at a median age of 35.5 years. Carriage of the TT genotype at the non-synonymous rs1884444 T > G relative to GG, was associated with a decreased risk of schistosomiasis-associated IRIS (OR, 0.25, 95% CI, 0.07-0.96, P = 0.043) while both baseline CD4+ cell counts and viral loads had no association with IRIS. Conclusion These findings indicate that the non-synonymous variant rs1884444 T > G of IL-23R is associated with a decreased risk to schistosomiasis-associated IRIS. However, additional studies in a larger cohort and with an all inclusive polymorphic variants in the synonymous and non-synonymous regions need to be evaluated.
    Full-text · Article · Jun 2014
    • "TNF-308*2 was not found in a small cohort of Australian HIV patients with IRD associated with non-tuberculous mycobacteria, but was present in 24–34% of controls (p = 0.015 − 0.035) [9]. The haplotype incorporating allele 2 at TNFA-308 and BAT1(int10) is present in Asians [16], so there is a clear dissociation between the role of TNF haplotypes in IRD associated with TB in the developing world (Table 1 ) and non-tuberculous mycobacteria in Aus- tralia [9]. Overall there were associations between polymorphisms in immune-related genes and TB-IRD, but none held in both ethnicities. "
    Full-text · Dataset · Sep 2013 · Disease markers
    • "TNF-308*2 was not found in a small cohort of Australian HIV patients with IRD associated with non-tuberculous mycobacteria, but was present in 24–34% of controls (p = 0.015 − 0.035) [9]. The haplotype incorporating allele 2 at TNFA-308 and BAT1(int10) is present in Asians [16], so there is a clear dissociation between the role of TNF haplotypes in IRD associated with TB in the developing world (Table 1 ) and non-tuberculous mycobacteria in Aus- tralia [9]. Overall there were associations between polymorphisms in immune-related genes and TB-IRD, but none held in both ethnicities. "
    [Show abstract] [Hide abstract] ABSTRACT: BACKGROUND: Up to 43% of HIV-infected patients co-infected with Mycobacterium tuberculosis experience exacerbations of tuberculosis (TB) after commencing antiretroviral therapy (ART). These are termed immune restoration disease (IRD). It is unclear why individual susceptibility varies. OBJECTIVE: We investigate if single nucleotide polymorphisms (SNP) in genes encoding cytokines, chemokines and their receptors associate with development of an IRD event in patients of two different ethnicities. METHODS: DNA samples were available from small well-characterised groups of HIV patients treated in Cambodia (TB-IRD, n = 17; HIV+TB+ controls, n = 55) and India (TB-IRD, n = 19; HIV+TB+ controls, n = 43). HIV patients with a TB diagnosis but no evidence of IRD were included to control for susceptibility to TB per se. Sixteen SNP implicated in inflammation or mycobacterial disease were genotyped. RESULTS: Susceptibility to TB-IRD associated with carriage of TNFA-1031*T (rs1799964; P=0.05) and SLC11A1 D543N*G (rs17235409; P=0.04) in Cambodian patients and carriage of IL18-607*G (rs1946518; P=0.02) and VDR FokI (F/f)*T (rs10735810; P=0.05) in Indian patients. CONCLUSIONS: Associations between polymorphisms in immune-related genes and TB-IRD were found, but none were common across two ethnicities.
    Full-text · Article · Apr 2013
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