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The role of G protein gene GNB3 C825T polymorphism in HIV-1 acquisition, progression and immune activation.

ABSTRACT: The GNB3 C825T polymorphism is associated with increased G protein-mediated signal transduction, SDF-1?-mediated lymphocyte chemotaxis, accelerated HIV-1 progression, and altered responses to antiretroviral therapy among Caucasian subjects. The GNB3 825T allele is highly prevalent in African populations, and as such any impact on HIV-1 acquisition or progression rates could have a dramatic impact. This study examines the association of the 825T polymorphism with HIV-1 acquisition, disease progression and immune activation in two African cohorts. GNB3 825 genotyping was performed for enrolees in both a commercial sex worker cohort and a perinatal HIV transmission (PHT) cohort in Nairobi, Kenya. Ex vivo immune activation was quantified by flow cytometry, and plasma chemokine levels were assessed by cytokine bead array.GNB3 genotype was not associated with sexual or vertical HIV-1 acquisition within these cohorts. Within the Pumwani cohort, GNB3 genotype did not affect HIV-1 disease progression among seroconverters or among HIV-1-positive individuals after adjustment for baseline CD4 count. Maternal CD4 decline and viral load increase in the PHT cohort did not differ between genotypes. Multi-parametric flow cytometry assessment of T cell activation (CD69, HLA-DR, CD38) and Treg frequency (CD25(+)FOXP3(+)) found no differences between genotype groups. Plasma SDF-1?, MIP-1? and TRAIL levels quantified by cytokine bead array were also similar between groups.In contrast to previous reports, we were unable to provide evidence to suggest that the GNB3 C825T polymorphism affects HIV-1 acquisition or disease progression within African populations. Ex vivo immune activation and plasma chemokine levels were similarly unaffected by GNB3 genotype in both HIV-1-negative and HIV-1-positive individuals. The paucity of studies investigating the impact of GNB3 polymorphism among African populations and the lack of mechanistic studies make it difficult to assess the true biological significance of this polymorphism in HIV-1 infection.

SUBMITTER: Juno J

PROVIDER: S-EPMC3278356 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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The role of G protein gene GNB3 C825T polymorphism in HIV-1 acquisition, progression and immune activation.

Juno Jennifer J Tuff Jeffrey J Choi Robert R Card Catherine C Kimani Joshua J Wachihi Charles C Koesters-Kiazyk Sandra S Ball T Blake TB Farquhar Carey C Plummer Francis A FA John-Stewart Grace G Luo Ma M Fowke Keith R KR

Retrovirology 20120103

<h4>Background</h4>The GNB3 C825T polymorphism is associated with increased G protein-mediated signal transduction, SDF-1α-mediated lymphocyte chemotaxis, accelerated HIV-1 progression, and altered responses to antiretroviral therapy among Caucasian subjects. The GNB3 825T allele is highly prevalent in African populations, and as such any impact on HIV-1 acquisition or progression rates could have a dramatic impact. This study examines the association of the 825T polymorphism with HIV-1 acquisit ...[more]

PMID: 22214232

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Project description:BACKGROUND:The C825T polymorphism (rs5443) of the Guanine Nucleotide-Binding protein subunit ?3 (GNB3) gene has been associated with obesity, essential hypertension, atherosclerosis, coronary diseases, and cerebrovascular events, but with some sex-specific effects. Its association with inflammatory mediators such as cell adhesion molecules has not been studied, although they are heavily involved in cardiovascular diseases' (CVDs) processes. The aim of our study was then to investigate a possible sex-specific effect of the GNB3 C825T polymorphism on serum soluble cell adhesion molecules such as E, P and L-selectins (sE, sP and sL-selectins). RESULTS:Participants were from the STANISLAS Family Study and were free of chronic disease as CVDs or cancer. We included in total 771 subjects aged 6 to 58 years (391 males (50.71%) and 380 females (49.29%)). No significant association of rs5443 was observed in the whole population with serum sE, sP and sL-selectins after adjusting for age, sex, body mass index, systolic blood pressure, anti-inflammatory drugs and hormonal drugs consumption. A significant interaction of rs5443 was observed with sex for sE-selectin (p?<?0.001), but not for sP and sL-selectins. After adjusting for covariables, the T allele was significantly associated with an additive increase effect on serum sE-selectin levels in males (??=?5.03?±?2.18; p?=?0.020), while a significant additive decrease effect was observed in females (??=-4.46?±?2.06; p?=?0.030). These associations stayed significant after correction for multiple tests (p?=?0.045 in males and in females). The additive phenotypic variance was 21.54% in males versus 1.91% in females. CONCLUSIONS:In our Caucasian population, the GNB3 C825T polymorphism showed a significant sex-specific effect on serum sE-selectin levels, with a disadvantage for males, as increased sE-selectin levels has been associated with CVDs outcomes. The T allele has been previously associated with the same CVDs as increased sE-selectin, but more often in males. The link we observed between this polymorphism and E-selectin is then consistent with previous findings, and helps to better understand the deleterious effect of the GNB3 825 T allele on CVDs outcomes in males. We revealed in this study an important pathway through which the GNB3 gene induces CVDs' outcomes.

Project description:BackgroundAlthough immune activation is associated with HIV acquisition, the nature of inflammatory profiles that increase HIV risk, which may include responses to M. tuberculosis (Mtb) infection, are not well characterized.MethodsWe conducted a nested case-control study using cryopreserved samples from persons who did and did not acquire HIV during the multinational Step clinical trial of the MRKAd5 HIV-1 vaccine. PBMCs from the last HIV-negative sample from incident HIV cases and controls were stimulated with Mtb-specific antigens (ESAT-6/CFP-10) and analyzed by flow cytometry with intracellular cytokine staining and scored with COMPASS. We measured inflammatory profiles with five Correlates of TB Risk (CoR) transcriptomic signatures. Our primary analysis examined the association of latent Mtb infection (LTBI; IFNγ+CD4+ T cell frequency) or RISK6 CoR signature with HIV acquisition. Conditional logistic regression analyses, adjusted for known predictors of HIV acquisition, were employed to assess whether TB-associated immune markers were associated with HIV acquisition.ResultsAmong 465 participants, LTBI prevalence (21.5% controls vs 19.1% cases, p = 0.51) and the RISK6 signature were not higher in those who acquired HIV. In exploratory analyses, Mtb antigen-specific polyfunctional CD4+ T cell COMPASS scores (aOR 0.96, 95% CI 0.77, 1.20) were not higher in those who acquired HIV. Two CoR signatures, Sweeney3 (aOR 1.38 (1.07, 1.78) per SD change) and RESPONSE5 (0.78 (0.61, 0.98)), were associated with HIV acquisition. The transcriptomic pattern used to differentiate active vs latent TB (Sweeney3) was most strongly associated with acquiring HIV.ConclusionsLTBI, Mtb polyfunctional antigen-specific CD4+ T cell activation, and RISK6 were not identified as risks for HIV acquisition. In exploratory transcriptomic analyses, two CoR signatures were associated with HIV risk after adjustment for known behavioral and clinical risk factors. We identified host gene expression signatures associated with HIV acquisition, but the observed effects are likely not mediated through Mtb infection.

Project description:PURPOSE OF REVIEW:This article explores new data from recent studies addressing the role of coinfections in immune activation in HIV-1-infected patients, with a focus on immune reconstitution inflammatory syndrome (IRIS), an aberrant inflammatory response occurring shortly after antiretroviral therapy (ART) initiation. RECENT FINDINGS:Chronic HIV infection is associated with several coinfections that contribute to immune activation in various settings including early after ART initiation in the most noticeable form of IRIS and also in chronic-treated infection, with chronic viral infections like cytomegalovirus and hepatitis C or hepatitis B virus contributing to immune activation and also morbidity and mortality. Expanding on older studies, the role of T cells in IRIS has been further elucidated with evidence of more pronounced effector activity in patients with IRIS that may be leading to excessive tissue disorder. Newer studies are also continuing to shed light on the role of myeloid cells as well as the contribution of antigen load in IRIS. In addition, preliminary data are beginning to suggest a possible role of inflammasome formation in IRIS. In cryptococcal IRIS, the role of activated immune cells (T cell and myeloid) and biomarkers were evaluated in more detail at the site of infection (cerebrospinal fluid). Finally, important differences of patients developing IRIS versus those who die from tuberculosis despite ART initiation were reported, a distinction that may have important implications for participant selection in studies aiming to prevent IRIS with immunosuppressive agents. SUMMARY:Better understanding of the role of opportunistic infections at ART initiation and IRIS pathogenesis will assist in improved strategies for prevention and treatment. The long-term consequences of IRIS remain unclear. Chronic viral coinfections with herpesviruses and hepatitis C virus are important factors in persistent immune activation in chronic-treated HIV.

Dataset Information

The role of G protein gene GNB3 C825T polymorphism in HIV-1 acquisition, progression and immune activation.

Publications

The role of G protein gene GNB3 C825T polymorphism in HIV-1 acquisition, progression and immune activation.

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