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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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Coreceptor abundance stratified by HIV disease stage and clade.The mean absolute number of CD4+/CCR5+ and CD4+/CXCR4+ T-cells (A) and mean density of CCR5 and CXCR4 on CD4+ cells (B) are shown, with error bars representing standard error of the means. Results are shown for samples from participants at early (black and heavy shading bars) or late (light shading and white bars) stages of infection and for participants infected with HIV-1 clade A (black and light shading bars) or D (heaving shading or white bars). *  =  p<0.05 and **  =  p<0.0001, calculated using unpaired t-test.
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pone-0019902-g002: Coreceptor abundance stratified by HIV disease stage and clade.The mean absolute number of CD4+/CCR5+ and CD4+/CXCR4+ T-cells (A) and mean density of CCR5 and CXCR4 on CD4+ cells (B) are shown, with error bars representing standard error of the means. Results are shown for samples from participants at early (black and heavy shading bars) or late (light shading and white bars) stages of infection and for participants infected with HIV-1 clade A (black and light shading bars) or D (heaving shading or white bars). *  =  p<0.05 and **  =  p<0.0001, calculated using unpaired t-test.

Mentions: We determined whether the abundance of HIV coreceptors, quantified by either the absolute number of total CD4+ T-cells expressing CCR5 or CXCR4, or their density on those cells, varied between clades or during the course of HIV infection. Prior to analysis each sample was gated on the CD3+/CD4+ cell population and statistical testing showed the majority of the coreceptor data obtained for this analysis was normally distributed (D'Agostino & Pearson omnibus normality test; data not shown). As a benchmark against which to compare results from HIV positive individuals, we determined the abundance of CCR5 and CXCR4 T-cells in four uninfected RCC participants. Absolute numbers of CD4+/CCR5+ and CD4+/CXCR4+ cells in HIV negative individuals were 99 cells/µl (55-143 95% C.I.) and 922 cells/µl (490-1354 95% C.I.) respectively. Analysing all HIV infected participants, there was 4.8 fold more CD4+ T-cells expressing CXCR4 (421 cells/µl [329-513]; mean [95% C.I.]) than CCR5 (19 cells/µl [13]–[25]; mean [95% C.I.]; p<0.0001, unpaired t-test). The mean number of CD4+/CCR5+ cells in participants at a late time point in HIV-1 infection was 2.2 fold lower compared to those at early stage groups, 12 and 26 respectively (p = 0.0113, unpaired t-test; Figure. 2A). The same trend was seen when comparing the mean number of CD4+ cells expressing the CXCR4 receptor in late vs. early stage groups. This was significantly higher in early stage HIV-1 infected participants than those at late time points (714 to 128 cells/µl; p<0.0001, unpaired t-test; Figure. 2A).


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)

Coreceptor abundance stratified by HIV disease stage and clade.The mean absolute number of CD4+/CCR5+ and CD4+/CXCR4+ T-cells (A) and mean density of CCR5 and CXCR4 on CD4+ cells (B) are shown, with error bars representing standard error of the means. Results are shown for samples from participants at early (black and heavy shading bars) or late (light shading and white bars) stages of infection and for participants infected with HIV-1 clade A (black and light shading bars) or D (heaving shading or white bars). *  =  p<0.05 and **  =  p<0.0001, calculated using unpaired t-test.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0019902-g002: Coreceptor abundance stratified by HIV disease stage and clade.The mean absolute number of CD4+/CCR5+ and CD4+/CXCR4+ T-cells (A) and mean density of CCR5 and CXCR4 on CD4+ cells (B) are shown, with error bars representing standard error of the means. Results are shown for samples from participants at early (black and heavy shading bars) or late (light shading and white bars) stages of infection and for participants infected with HIV-1 clade A (black and light shading bars) or D (heaving shading or white bars). *  =  p<0.05 and **  =  p<0.0001, calculated using unpaired t-test.
Mentions: We determined whether the abundance of HIV coreceptors, quantified by either the absolute number of total CD4+ T-cells expressing CCR5 or CXCR4, or their density on those cells, varied between clades or during the course of HIV infection. Prior to analysis each sample was gated on the CD3+/CD4+ cell population and statistical testing showed the majority of the coreceptor data obtained for this analysis was normally distributed (D'Agostino & Pearson omnibus normality test; data not shown). As a benchmark against which to compare results from HIV positive individuals, we determined the abundance of CCR5 and CXCR4 T-cells in four uninfected RCC participants. Absolute numbers of CD4+/CCR5+ and CD4+/CXCR4+ cells in HIV negative individuals were 99 cells/µl (55-143 95% C.I.) and 922 cells/µl (490-1354 95% C.I.) respectively. Analysing all HIV infected participants, there was 4.8 fold more CD4+ T-cells expressing CXCR4 (421 cells/µl [329-513]; mean [95% C.I.]) than CCR5 (19 cells/µl [13]–[25]; mean [95% C.I.]; p<0.0001, unpaired t-test). The mean number of CD4+/CCR5+ cells in participants at a late time point in HIV-1 infection was 2.2 fold lower compared to those at early stage groups, 12 and 26 respectively (p = 0.0113, unpaired t-test; Figure. 2A). The same trend was seen when comparing the mean number of CD4+ cells expressing the CXCR4 receptor in late vs. early stage groups. This was significantly higher in early stage HIV-1 infected participants than those at late time points (714 to 128 cells/µl; p<0.0001, unpaired t-test; Figure. 2A).

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