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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

Individual profiles for all cytokines and chemokines measured.Vertical scatter plots show the median plasma concentration (horizontal black line; pg/ml) for the anti-HIV-1 cytokines (IFNγ, TNFα, IL-2, IL-10, IL-5 and IL-4) and chemokines (MIP-1α, MIP-1β and RANTES) measured as part of this study. Participants were analysed in four groups based on disease stage and HIV clade: Early-A, Early-D, Late-A and Late-D. *  =  p<0.05 and **  =  p<0.0001, calculated using Mann Whitney test.
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pone-0019902-g004: Individual profiles for all cytokines and chemokines measured.Vertical scatter plots show the median plasma concentration (horizontal black line; pg/ml) for the anti-HIV-1 cytokines (IFNγ, TNFα, IL-2, IL-10, IL-5 and IL-4) and chemokines (MIP-1α, MIP-1β and RANTES) measured as part of this study. Participants were analysed in four groups based on disease stage and HIV clade: Early-A, Early-D, Late-A and Late-D. *  =  p<0.05 and **  =  p<0.0001, calculated using Mann Whitney test.

Mentions: Median concentrations of individual cytokines and chemokines were analysed across the four groups: Early-A, Early-D, Late-A and Late-D. These revealed comparable levels in the majority of participants. The range of median concentrations was 0–11.1 pg/ml (Figure 4) apart from IFNγ (50.70 pg/ml; Figure 4A), MIP-1β (53.39 pg/ml; Figure 4E) and RANTES (10611 pg/ml; Figure 4F). However, IFNγ levels in participants in the Late-D group were lower than those in Late-A (45.8 vs 68.7 pg/ml; p = 0.0065; Figure 4A). A similar pattern was observed when we measured IL-2 (0.0 vs 9.9 pg/ml; p = 0.0087; Figure 4C). Finally, there was a significant decrease in MIP-1β as the course of HIV disease progressed (81.9 vs 26.7 pg/ml; p = 0.0022; Figure 4E).


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)

Individual profiles for all cytokines and chemokines measured.Vertical scatter plots show the median plasma concentration (horizontal black line; pg/ml) for the anti-HIV-1 cytokines (IFNγ, TNFα, IL-2, IL-10, IL-5 and IL-4) and chemokines (MIP-1α, MIP-1β and RANTES) measured as part of this study. Participants were analysed in four groups based on disease stage and HIV clade: Early-A, Early-D, Late-A and Late-D. *  =  p<0.05 and **  =  p<0.0001, calculated using Mann Whitney test.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0019902-g004: Individual profiles for all cytokines and chemokines measured.Vertical scatter plots show the median plasma concentration (horizontal black line; pg/ml) for the anti-HIV-1 cytokines (IFNγ, TNFα, IL-2, IL-10, IL-5 and IL-4) and chemokines (MIP-1α, MIP-1β and RANTES) measured as part of this study. Participants were analysed in four groups based on disease stage and HIV clade: Early-A, Early-D, Late-A and Late-D. *  =  p<0.05 and **  =  p<0.0001, calculated using Mann Whitney test.
Mentions: Median concentrations of individual cytokines and chemokines were analysed across the four groups: Early-A, Early-D, Late-A and Late-D. These revealed comparable levels in the majority of participants. The range of median concentrations was 0–11.1 pg/ml (Figure 4) apart from IFNγ (50.70 pg/ml; Figure 4A), MIP-1β (53.39 pg/ml; Figure 4E) and RANTES (10611 pg/ml; Figure 4F). However, IFNγ levels in participants in the Late-D group were lower than those in Late-A (45.8 vs 68.7 pg/ml; p = 0.0065; Figure 4A). A similar pattern was observed when we measured IL-2 (0.0 vs 9.9 pg/ml; p = 0.0087; Figure 4C). Finally, there was a significant decrease in MIP-1β as the course of HIV disease progressed (81.9 vs 26.7 pg/ml; p = 0.0022; Figure 4E).

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