Interleukin-10 Promoter Polymorphisms Influence HIV-1 Susceptibility and Primary HIV-1 Pathogenesis

Hasso Plattner Research Laboratory, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa.
The Journal of Infectious Diseases (Impact Factor: 5.78). 07/2009; 200(3):448-52. DOI: 10.1086/600072
Source: PubMed

ABSTRACT Interleukin (IL)-10 directly inhibits human immunodeficiency virus type 1 (HIV-1) replication, but it may also promote viral persistence by inactivation of effector immune mechanisms. Here, we show in an African cohort that individuals with genotypes associated with high IL-10 production at 2 promoter single-nucleotide polymorphisms (-1082 and -592) were less likely to become HIV-1 infected but had significantly higher median plasma viral loads during the acute phase (<or=3 months after infection). However, as the infection progressed, the association between genotype and median viral load was reversed. Thus, IL-10 may influence HIV-1 susceptibility and pathogenesis, but effects on the latter may differ according to the infection phase.

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Available from: Salim S Abdool Karim, Jul 01, 2014
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    • "In particular, two large studies investigating various ethnicities and exposure routes have not found any significant correlations between -592C/A and HIV acquisition (Shin et al., 2000; Shrestha et al., 2006). Two smaller reports, however, have found a detrimental effect of -592A allele or -592A allele containing haplotypes or genotypes on HIV susceptibility in African-American and North-Indian populations (Chatterjee et al., 2009; Naicker et al., 2009). The disadvantageous effect of -592A allele or AA genotypes have also been described in several studies in the context of HIV disease progression (Chatterjee et al., 2009; Oleksyk et al., 2009; Shin et al., 2000). "
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    ABSTRACT: Interleukin 10 (IL-10) is a multifunctional cytokine produced by macrophages, monocytes, and T-helper cells. Two polymorphisms at positions -592 and -1082 have been associated with HIV susceptibility. However, their associations with susceptibility to HIV and its co-infections among intravenous drug users (IDUs) are largely unknown. A total of 345 IDUs were recruited. Of the 173 HIV negative IDUs, 20 were classified as highly exposed HIV seronegative subjects (HESNs). A control group consisted of 496 blood donors; all HIV, HCV, and HBV negative. The IL-10 -592C/A and -1082A/G were determined using TaqMan allelic discrimination assay. Of the IDUs, 50% were HIV positive, 89% HCV positive, 67% HBV positive and 41% had triple infection. IL-10 -592C allele and -1082A allele were the most common and the -1082 AG/-592CC was the most common genotype pair. All HESNs exhibited -1082A allele as compared to 81.4% of the HIV positive IDUs and 79% of donors (p=0.029 and p=0.019, respectively). None of HESNs had GG/CC genotype pair compared with 18.6% of HIV+ IDUs and 21.0% of donors (p=0.029 and p=0.019, respectively). The possession of -592AC and genotype pair AG/AC were associated with the decreased odds of HBV infection (OR=0.28; 95% CI 0.09-0.87; p=0.028 and OR=0.19; 95% CI 0.06-0.61; p=0.052, respectively). The presence of low producing IL-10 -1082A and -592A alleles and their containing genetic variants protect highly exposed IDUs against acquisition of HIV and HBV infections. Copyright © 2014. Published by Elsevier B.V.
    Infection, genetics and evolution: journal of molecular epidemiology and evolutionary genetics in infectious diseases 12/2014; 30. DOI:10.1016/j.meegid.2014.12.023 · 3.26 Impact Factor
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    • "Recently, the immunoregulatory cytokine IL-10 was identified as playing a key role in suppressing antiviral immune responses, leading to viral persistence [34] [35]. A study in South Africa populations indicated that individuals carrying the IL-10- 592AA genotype were more likely to become HIV-1 infected further; these results generally suggested that IL-10 promoter polymorphisms were linked to low IL-10 production and associated with increased HIV-1 susceptibility [36]. A study in Kenya revealed pathological interactions between HIV and malaria in dually infected patients, but the public health implications of the interplay have remained unclear [37]. "
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    ABSTRACT: Sub-Saharan Africa has continued leading in prevalence and incidence of major infectious disease killers such as HIV/AIDS, tuberculosis, and malaria. Epidemiological triad of infectious diseases includes susceptible host, pathogen, and environment. It is imperative that all aspects of vertices of the infectious disease triad are analysed to better understand why this is so. Studies done to address this intriguing reality though have mainly addressed pathogen and environmental components of the triad. Africa is the most genetically diverse region of the world as well as being the origin of modern humans. Malaria is relatively an ancient infection in this region as compared to TB and HIV/AIDS; from the evolutionary perspective, we would draw lessons that this ancestrally unique population now under three important infectious diseases both ancient and exotic will be skewed into increased genetic diversity; moreover, other evolutionary forces are also still at play. Host genetic diversity resulting from many years of malaria infection has been well documented in this population; we are yet to account for genetic diversity from the trio of these infections. Effect of host genetics on treatment outcome has been documented. Host genetics of sub-Saharan African population and its implication to infectious diseases are an important aspect that this review seeks to address.
    08/2014; 2014(108291). DOI:10.1155/2014/108291
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    • "BST-2 can be added to the list of virus restriction factors, which includes TRIM5a, APOBEC3G, SAMHD1, and IL10, which all appear to have a role in HIV-1 infection and disease progression. In South Africa, variants in IL10 and APO- BEC3G genes have been associated with increased risk of HIV-1 infection and disease progression, respectively, through association studies (Naicker et al., 2009, Reddy et al., 2010). A recent study on the BST-2 gene showed the promoter polymorphism rs3217318, a 19 bp insertion allele at position -411, to be a risk factor for HIV-1/AIDS disease progression in a Spanish cohort of male IDUs (Laplana et al., 2013). "
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    ABSTRACT: Abstract The present study reports promoter variants in four sub-Saharan African populations that may affect BST-2 gene regulation. Recently, an in/del within the BST-2 promoter has been associated with HIV-1 disease progression in a Spanish cohort. Hence, we sequenced the proximal promoter region of the BST-2 gene in 581 individuals from South Africa, Zimbabwe, Malawi, and Cameroon. Seven SNPs were identified: rs28413176 (+26i6/Δ6); rs28413175 (-160i1/Δ1), -187A>G (nucleotide position -17516614); rs28413174 (-193G>A); rs73921425 (-199G>A); rs12609479 (-201C>T); and rs112492472 (-225C>T). The -199A and -225T alleles showed interesting trends across the sub-Saharan continent. Using predictive bioinformatics tools, we show that allelic variation at -199 and -201 potentially affect key transcription factor binding sites including bHLH, c-Myb, and E47. Importantly, data available from the ENCODE study gave further credence to our hypothesis of transcriptional regulation of BST-2 by a bHLH TF such as Mxi1. The possible repressive transcriptional effect of Mxi1 combined with the allelic frequency trend seen at -199 between African populations overlays well with current HIV-1 prevalence data, and may be a contributing factor to this phenomenon. The differences in HIV-1 prevalence in African countries could be, in part, due to distribution of genetic variants that affect susceptibility to HIV-1. Our findings therefore have substantive value for the design of future diagnostics for global health oriented diagnostics for HIV-1 susceptibility, and rational therapeutics on the critical path to personalized medicine in the African continent. As HIV-1 epidemiology vastly impacts human populations around the world, the population genomics strategy we have utilized herein can have value for other global regions as well.
    Omics: a journal of integrative biology 03/2014; DOI:10.1089/omi.2013.0127 · 2.73 Impact Factor
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