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. 2012 Jan 3:9:1.
doi: 10.1186/1742-4690-9-1.

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

Jennifer Juno  1 , Jeffrey Tuff, Robert Choi, Catherine Card, Joshua Kimani, Charles Wachihi, Sandra Koesters-Kiazyk, T Blake Ball, Carey Farquhar, Francis A Plummer, Grace John-Stewart, Ma Luo, Keith R Fowke
Affiliations

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

Jennifer Juno et al. Retrovirology. .

Abstract

Background: 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 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.

Results: 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-1α, MIP-1β and TRAIL levels quantified by cytokine bead array were also similar between groups.

Conclusions: 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.

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Figures

Figure 1
Figure 1
Kaplan-Meier survival analysis of time from enrolment to seroconversion in Pumwani cohort participants. 277 individuals with a known date of seroconversion were included in this analysis: 99 GNB3 825CC/CT and 178 GNB3 825TT. There was no difference in time to seroconversion as determined by Cox proportional hazard regression [Hazard Ratio (HR) 1.313, 95% CI 0.910, 1.895, p = 0.15]. Icons between drops in the lines represent the end of an individual's data set (censoring event).
Figure 2
Figure 2
Kaplan-Meier survival analysis of HIV disease progression to CD4 count < 350 cells/uL among. (A) 73 CSW cohort participants who seroconverted during follow-up: 21 GNB3 825CC/CT subjects and 52 GNB3 825TT subjects. There were no significant differences in time to CD4 < 350 as determined by Cox proportional hazard analysis [HR 0.665, 95% CI 0.369, 1.198, p = 0.1742]. (B) 146 HIV-1-positive CSW cohort subjects: 48 GNB3 825CC/CT subjects and 98 GNB3 825TT subjects. Following adjustment for baseline CD4 count, there were no significant differences in time to CD4 < 350 as determined by Cox proportional hazard analysis [HR = 0.956, 95% CI 0.619, 1.477, p = 0.8397]. (C) 262 PHT cohort HIV-1-positive mothers: 125 GNB3 825CC/CT subjects and 137 GNB3 825TT subjects. Following adjustment for baseline CD4 count, there were no significant differences in time to CD4 < 350 as determined by Cox proportional hazard analysis [HR = 0.75, 95% CI 0.47, 1.19, p = 0.22].
Figure 3
Figure 3
Expression of ex vivo cell surface markers measured by flow cytometry among HIV-1-negative subjects. (A) Expression of CD69, HLA-DR, CD38 and regulatory T cells (Tregs; defined as CD3+CD4+CD25+FOXP3+) among HIV-1-negative CSW cohort subjects. Values are expressed as a percentage of the parental CD4+ or CD8+ T cell population, as indicated. CD38 and HLA-DR plots are representative of two distinct studies. There were no significant differences in expression levels between GNB3 825CC/CT and 825TT groups as measured by Mann-Whitney test [p > 0.1 for all]. (B) Expression of HIV-1 co-receptors CCR5 and CXCR4 expressed as a percentage of the parental CD4+ T cell population. There were no significant differences in expression levels or CCR5 median fluorescence intensity (MFI) between GNB3 825CC/CT and 825TT groups as measured by Mann-Whitney test [p > 0.1 for all]. (C) Expression of activation markers CD69 and HLA DR on CD4+CCR5+ T cells. There were no significant differences in expression levels between GNB3 825CC/CT and 825TT groups as measured by Mann-Whitney test [p > 0.1 for all].
Figure 4
Figure 4
Expression of ex vivo cell surface markers among HIV-1-positive subjects. Expression of IL-7Rα, Fas, CD69, HLA-DR, and CD38 was among HIV-1-positive CSW cohort participants. Values are expressed as a percentage of the parental (A) CD4+ or (B) CD8+ T cell population, as indicated. CD69 plots are representative of two distinct studies, CD38 plots represent three distinct studies and HLA-DR plots represent four distinct studies. There were no significant differences in expression levels between GNB3 825CC/CT and 825TT groups as measured by Mann-Whitney test [p > 0.1 for all].
Figure 5
Figure 5
Quantification of plasma cytokine/chemokine levels. Plasma SDF-1α, MIP-1β and TRAIL concentrations were quantified by Milliplex bead assay among HIV-1-positive women of the CSW cohort. No significant differences in concentration between GNB3 825CC/CT and 825TT groups were detected by Mann-Whitney test [p = 0.14 for SDF-1α, p = 0.88 for MIP-1β, p = 0.31 for TRAIL].
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