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Coreceptor and cytokine concentrations may not explain differences in disease progression observed in HIV-1 clade A and D infected Ugandans.

Wright E, Mugaba S, Grant P, Parkes-Ratanshi R, Van der Paal L, Grosskurth H, Kaleebu P - PLoS ONE (2011)

Bottom Line: Across all participants we observed significantly higher concentration of Th(1) cytokines compared to Th(2) (66.4 vs 23.8 pg/ml; p<0.0001).Plasma concentrations of IFNγ and IL-2 were 1.8 and 2.4 fold lower respectively in Late-D infected participants compared to Late-A participants.MIP-1β levels also decreased from 118.0 pg/ml to 47.1 pg/ml (p = 0.0396) as HIV disease progressed.

View Article: PubMed Central - PubMed

Affiliation: MRC/UVRI Uganda Research Unit on AIDS, Uganda Virus Research Institute, Entebbe, Uganda. edward.wright@ucl.ac.uk

ABSTRACT

Background: The use of cellular coreceptors and modulation of cytokine concentrations by HIV to establish a productive infection is well documented. However, it is unknown whether the expression of these proteins affects the course of HIV clade A and D disease, reported to have different progression rates.

Methodology/principal findings: We investigated whether the number of CD4(+) T-cells expressing CCR5 or CXCR4, the density of these coreceptors and concentrations of specific immune proteins linked to HIV pathogenesis vary between individuals infected with HIV clade A or D. We undertook additional analyses stratifying participants by early (CD4>500 cells/µl) or late (CD4<200 cells/µl) disease stage. Whole blood samples were taken from 50 HIV-1 infected individuals drawn from cohorts in rural south-west Uganda. Late stage participants had less than half the number of CD4(+)/CCR5(+) T-cells (p = 0.0113) and 5.6 times fewer CD4(+)/CXCR4(+) cells (p<0.0001) than early stage participants. There was also a statistically significant difference in the density of CXCR4 on CD4(+) cells between clade A and D infected early stage participants (142 [A] vs 84 [D]; p = 0.0146). Across all participants we observed significantly higher concentration of Th(1) cytokines compared to Th(2) (66.4 vs 23.8 pg/ml; p<0.0001). Plasma concentrations of IFNγ and IL-2 were 1.8 and 2.4 fold lower respectively in Late-D infected participants compared to Late-A participants. MIP-1β levels also decreased from 118.0 pg/ml to 47.1 pg/ml (p = 0.0396) as HIV disease progressed.

Conclusions/significance: We observed specific alterations in the abundance of CD4(+)/CCR5(+) and CD4(+)/CXCR4(+) T-cells, and concentrations of immune proteins across different HIV clades and as infection progresses. Our results suggest that these changes are unlikely to explain the observed differences in disease progression between subtype A and D infections. However, our observations further the understanding of the natural progression of non-clade B HIV infection and how the virus adapts to exploit the host environment.

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Related in: MedlinePlus

Total cytokine concentrations in study participants.Bar graphs represent cytokines concentrations (pg/ml) as a proportion of the total concentration of Th1 and Th2 cytokines measured. These have been stratified by HIV-1 disease stage (A) or HIV-1 clade (B) with shaded and patterned areas corresponding to Th1 and Th2 cytokines respectively. **  =  p<0.0001 (Mann Whitney test) for total Th1 vs Th2 cytokines when compared across all HIV positive study participants (n = 50).
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pone-0019902-g003: Total cytokine concentrations in study participants.Bar graphs represent cytokines concentrations (pg/ml) as a proportion of the total concentration of Th1 and Th2 cytokines measured. These have been stratified by HIV-1 disease stage (A) or HIV-1 clade (B) with shaded and patterned areas corresponding to Th1 and Th2 cytokines respectively. **  =  p<0.0001 (Mann Whitney test) for total Th1 vs Th2 cytokines when compared across all HIV positive study participants (n = 50).

Mentions: As other cell surface molecules and cytokines are known to influence the clinical course of HIV-1 disease progression and the expression of HIV CCR5 and CXCR4 coreceptors, we measured the level of certain anti-HIV-1 cytokines (IFNγ, TNFα, IL-2, IL-10, IL-5 and IL-4) and chemokines (MIP-1α, MIP-1β, RANTES) in the plasma of each study participant. Most of the cytokine data was not normally distributed (D'Agostino & Pearson omnibus normality test; data not shown) so median values and corresponding significance tests were used for the analysis. These revealed that the combined concentrations of Th1 cytokines in all participants was significantly higher than Th2 concentrations (66.4 vs 23.9 pg/ml; p<0.0001, Mann Whitney test; Figure 3). The observed increase in Th1 cytokines (62.7 vs 71.0 pg/ml) and slight decrease in Th2 cytokines (24.6 vs 23.1 pg/ml) in individuals at the late stage of HIV disease when comparing with those at the early stage, were not significant (p = 0.4728 and p = 0.7269 respectively, Mann Whitney test; Figure 3A). There was a small decrease in the concentration of Th1 cytokines (58.6 [D] vs 63.9 [A] pg/ml) and similar levels of Th2 cytokines (25.5 [D] vs 25.9 [A] pg/ml) in clade D infected participants compared to clade A infected (Figure 3B). However, neither variation was significant.


Coreceptor and cytokine concentrations may not explain differences in disease progression observed in HIV-1 clade A and D infected Ugandans.

Wright E, Mugaba S, Grant P, Parkes-Ratanshi R, Van der Paal L, Grosskurth H, Kaleebu P - PLoS ONE (2011)

Total cytokine concentrations in study participants.Bar graphs represent cytokines concentrations (pg/ml) as a proportion of the total concentration of Th1 and Th2 cytokines measured. These have been stratified by HIV-1 disease stage (A) or HIV-1 clade (B) with shaded and patterned areas corresponding to Th1 and Th2 cytokines respectively. **  =  p<0.0001 (Mann Whitney test) for total Th1 vs Th2 cytokines when compared across all HIV positive study participants (n = 50).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3104992&req=5

pone-0019902-g003: Total cytokine concentrations in study participants.Bar graphs represent cytokines concentrations (pg/ml) as a proportion of the total concentration of Th1 and Th2 cytokines measured. These have been stratified by HIV-1 disease stage (A) or HIV-1 clade (B) with shaded and patterned areas corresponding to Th1 and Th2 cytokines respectively. **  =  p<0.0001 (Mann Whitney test) for total Th1 vs Th2 cytokines when compared across all HIV positive study participants (n = 50).
Mentions: As other cell surface molecules and cytokines are known to influence the clinical course of HIV-1 disease progression and the expression of HIV CCR5 and CXCR4 coreceptors, we measured the level of certain anti-HIV-1 cytokines (IFNγ, TNFα, IL-2, IL-10, IL-5 and IL-4) and chemokines (MIP-1α, MIP-1β, RANTES) in the plasma of each study participant. Most of the cytokine data was not normally distributed (D'Agostino & Pearson omnibus normality test; data not shown) so median values and corresponding significance tests were used for the analysis. These revealed that the combined concentrations of Th1 cytokines in all participants was significantly higher than Th2 concentrations (66.4 vs 23.9 pg/ml; p<0.0001, Mann Whitney test; Figure 3). The observed increase in Th1 cytokines (62.7 vs 71.0 pg/ml) and slight decrease in Th2 cytokines (24.6 vs 23.1 pg/ml) in individuals at the late stage of HIV disease when comparing with those at the early stage, were not significant (p = 0.4728 and p = 0.7269 respectively, Mann Whitney test; Figure 3A). There was a small decrease in the concentration of Th1 cytokines (58.6 [D] vs 63.9 [A] pg/ml) and similar levels of Th2 cytokines (25.5 [D] vs 25.9 [A] pg/ml) in clade D infected participants compared to clade A infected (Figure 3B). However, neither variation was significant.

Bottom Line: Across all participants we observed significantly higher concentration of Th(1) cytokines compared to Th(2) (66.4 vs 23.8 pg/ml; p<0.0001).Plasma concentrations of IFNγ and IL-2 were 1.8 and 2.4 fold lower respectively in Late-D infected participants compared to Late-A participants.MIP-1β levels also decreased from 118.0 pg/ml to 47.1 pg/ml (p = 0.0396) as HIV disease progressed.

View Article: PubMed Central - PubMed

Affiliation: MRC/UVRI Uganda Research Unit on AIDS, Uganda Virus Research Institute, Entebbe, Uganda. edward.wright@ucl.ac.uk

ABSTRACT

Background: The use of cellular coreceptors and modulation of cytokine concentrations by HIV to establish a productive infection is well documented. However, it is unknown whether the expression of these proteins affects the course of HIV clade A and D disease, reported to have different progression rates.

Methodology/principal findings: We investigated whether the number of CD4(+) T-cells expressing CCR5 or CXCR4, the density of these coreceptors and concentrations of specific immune proteins linked to HIV pathogenesis vary between individuals infected with HIV clade A or D. We undertook additional analyses stratifying participants by early (CD4>500 cells/µl) or late (CD4<200 cells/µl) disease stage. Whole blood samples were taken from 50 HIV-1 infected individuals drawn from cohorts in rural south-west Uganda. Late stage participants had less than half the number of CD4(+)/CCR5(+) T-cells (p = 0.0113) and 5.6 times fewer CD4(+)/CXCR4(+) cells (p<0.0001) than early stage participants. There was also a statistically significant difference in the density of CXCR4 on CD4(+) cells between clade A and D infected early stage participants (142 [A] vs 84 [D]; p = 0.0146). Across all participants we observed significantly higher concentration of Th(1) cytokines compared to Th(2) (66.4 vs 23.8 pg/ml; p<0.0001). Plasma concentrations of IFNγ and IL-2 were 1.8 and 2.4 fold lower respectively in Late-D infected participants compared to Late-A participants. MIP-1β levels also decreased from 118.0 pg/ml to 47.1 pg/ml (p = 0.0396) as HIV disease progressed.

Conclusions/significance: We observed specific alterations in the abundance of CD4(+)/CCR5(+) and CD4(+)/CXCR4(+) T-cells, and concentrations of immune proteins across different HIV clades and as infection progresses. Our results suggest that these changes are unlikely to explain the observed differences in disease progression between subtype A and D infections. However, our observations further the understanding of the natural progression of non-clade B HIV infection and how the virus adapts to exploit the host environment.

Show MeSH
Related in: MedlinePlus