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: 6). 07/2009; 200(3):448-52. DOI: 10.1086/600072
Source: PubMed


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 · 3.02 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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    • "IL-10 is a pleiotropic cytokine that has immunomodulatory effects especially in down-regulating pro-inflammatory cytokines and costimulatory molecules, as well as major histocompatibility complex (MHC) class II proteins [17]. IL-10 has been associated with disease progression to AIDS but its role is still not clearly defined [18], [19], [20], [21]. In addition, recent studies have indicated that IL-15, which enhances innate and adaptive immunity by acting on CD8+T and natural killer cells, may play a role during acute HIV/SIV infection by impacting viremia and viral set point [16], [22], [23]. "
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    ABSTRACT: Little is known about the effects of Major Histocompatibility Complex (MHC) haplotypes on immunity to primate lentiviruses involving both acquired and innate immune responses. We present statistical evidence of the influence of MHC polymorphism on antiviral immunity of Mauritian cynomolgus macaques (MCM) following simian/human immunodeficiency virus SHIVSF162P4cy infection, involving the production of pro- and anti-inflammatory cytokines and α-defensins, which may modulate acquired immune responses. During the acute phase of infection, IL-10 correlated positively with viral load and negatively with CD4+T cell counts. Furthermore, α-defensins production was directly correlated with plasma viral RNA, particularly at peak of viral load. When the effects of the MHC were analyzed, a significant association between lower anti-Env binding and neutralizing antibody levels with class IB M4 haplotype and with class IA, IB M4 haplotype, respectively, was observed in the post-acute phase. Lower antibody responses may have resulted into a poor control of infection thus explaining the previously reported lower CD4 T cell counts in these monkeys. Class II M3 haplotype displayed significantly lower acute and post-acute IL-10 levels. In addition, significantly lower levels of α-defensins were detected in class IA M3 haplotype monkeys than in non-M3 macaques, in the post-acute phase of infection. These data indicate that the MHC could contribute to the delicate balance of pro-inflammatory mechanisms, particularly with regard to the association between IL-10 and α-defensins in lentivirus infection. Our results show that host genetic background, virological and immunological parameters should be considered for the design and interpretation of HIV-1 vaccine efficacy studies.
    PLoS ONE 04/2014; 9(4):e93235. DOI:10.1371/journal.pone.0093235 · 3.23 Impact Factor
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