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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

Radial tree showing degree of identity between the study participants' HIV isolates.RT-PCR was undertaken to amplify sequence from the reverse transcripase gene that was subsequently used to construct the tree. The branch lengths and scale correspond to the number of substitutions/mutations per site.
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pone-0019902-g001: Radial tree showing degree of identity between the study participants' HIV isolates.RT-PCR was undertaken to amplify sequence from the reverse transcripase gene that was subsequently used to construct the tree. The branch lengths and scale correspond to the number of substitutions/mutations per site.

Mentions: For analyses participants were placed into one of fours groups according to disease stage and HIV subtype: Early-A, Early-D, Late-A and Late-D. Of the 50 participants enrolled in this study clades A and D were the only subtypes present (25 participants each; Figure 1). Sixty percent of early stage participants were infected with clade A while this was reversed in the late stage group with 60% infected with clade D (Table 1). The mean CD4+ count for early stage individuals was 736 cells/µl (95% confidence interval [C.I.] 663–808) compared to 146 cells/µl (95% C.I. 122–169) for the late stage group. The CD4+ counts were similar for A and D infected participants at both time points (Table 1). As expected the mean CD4+ count in HIV negative participants was much higher (950 cells/µl [95% C.I. 513–1388]; n = 4). There was a similar age distribution between the four groups, with the Early-D group having the highest (40.3 [32.1–48.4]; mean age [95% C.I.] in years). There were more females than males in the late group (64% vs 36%) but this was skewed by the Late-A group comprising 90% females, a chance result due to the sampling strategy used. As expected, individuals in the late group were also at more advanced stages of HIV disease according to WHO staging compared to early individuals (Early  =  2.2 [1.8–2.6], Late  =  2.8 [2.5–3.1]; mean stage [95% C.I.] in years). The infecting subtype did not affect WHO disease staging. There was a statically significant difference in HIV viral load measurements between participants in early versus late time points (early: 14,021 [4058–23983]; mean viral load [95% C.I.]. Late: (132,203 [44,944–219462]; mean viral load [95% C.I.]. p = 0.0126; unpaired t-test). While there was a trend for the Early-D and Late-D groups to have higher viral load measurements than the corresponding clade A infected groups, this difference was not significant (Table 1).


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)

Radial tree showing degree of identity between the study participants' HIV isolates.RT-PCR was undertaken to amplify sequence from the reverse transcripase gene that was subsequently used to construct the tree. The branch lengths and scale correspond to the number of substitutions/mutations per site.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0019902-g001: Radial tree showing degree of identity between the study participants' HIV isolates.RT-PCR was undertaken to amplify sequence from the reverse transcripase gene that was subsequently used to construct the tree. The branch lengths and scale correspond to the number of substitutions/mutations per site.
Mentions: For analyses participants were placed into one of fours groups according to disease stage and HIV subtype: Early-A, Early-D, Late-A and Late-D. Of the 50 participants enrolled in this study clades A and D were the only subtypes present (25 participants each; Figure 1). Sixty percent of early stage participants were infected with clade A while this was reversed in the late stage group with 60% infected with clade D (Table 1). The mean CD4+ count for early stage individuals was 736 cells/µl (95% confidence interval [C.I.] 663–808) compared to 146 cells/µl (95% C.I. 122–169) for the late stage group. The CD4+ counts were similar for A and D infected participants at both time points (Table 1). As expected the mean CD4+ count in HIV negative participants was much higher (950 cells/µl [95% C.I. 513–1388]; n = 4). There was a similar age distribution between the four groups, with the Early-D group having the highest (40.3 [32.1–48.4]; mean age [95% C.I.] in years). There were more females than males in the late group (64% vs 36%) but this was skewed by the Late-A group comprising 90% females, a chance result due to the sampling strategy used. As expected, individuals in the late group were also at more advanced stages of HIV disease according to WHO staging compared to early individuals (Early  =  2.2 [1.8–2.6], Late  =  2.8 [2.5–3.1]; mean stage [95% C.I.] in years). The infecting subtype did not affect WHO disease staging. There was a statically significant difference in HIV viral load measurements between participants in early versus late time points (early: 14,021 [4058–23983]; mean viral load [95% C.I.]. Late: (132,203 [44,944–219462]; mean viral load [95% C.I.]. p = 0.0126; unpaired t-test). While there was a trend for the Early-D and Late-D groups to have higher viral load measurements than the corresponding clade A infected groups, this difference was not significant (Table 1).

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