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Published on: January 5, 2016
Coreceptor and cytokine concentrations may not explain differences in disease progression observed in HIV-1 clade A
Edward Wright1, Susan Mugaba, Paul Grant
1MRC/UVRI Uganda Research Unit on AIDS, Uganda Virus Research Institute, Entebbe, Uganda. edward.wright@ucl.ac.uk
Insights
HIV infection alters CD4 T-cells and immune proteins, but these changes don't fully explain disease differences between clades A and D. This study enhances understanding of non-clade B HIV progression.
Area of Science:
- Immunology
- Virology
- Infectious Diseases
Background:
- HIV utilizes cellular coreceptors and modulates cytokine concentrations for productive infection.
- The impact of coreceptor expression on HIV clade A and D disease progression, known for differing rates, remains unclear.
Purpose of the Study:
- To investigate variations in CD4(+) T-cell coreceptor expression (CCR5, CXCR4) and immune protein concentrations between HIV clade A and D infections.
- To analyze these variations in relation to disease stage (early vs. late).
Main Methods:
- Analysis of whole blood samples from 50 HIV-1 infected individuals in Uganda.
- Quantification of CD4(+) T-cells expressing CCR5 and CXCR4.
- Measurement of coreceptor density and plasma concentrations of immune proteins (cytokines like IFNγ, IL-2, MIP-1β).
- Stratification by disease stage (CD4 count >500 cells/µl vs. <200 cells/µl) and HIV clade (A vs. D).
Main Results:
- Late-stage HIV infection showed significantly fewer CD4(+)/CCR5(+) and CD4(+)/CXCR4(+) T-cells compared to early-stage.
- A significant difference in CXCR4 density on CD4(+) cells was observed between early-stage clade A and D infections.
- Higher concentrations of Th(1) cytokines compared to Th(2) were noted across all participants.
- Late-stage clade D infections had lower plasma concentrations of IFNγ and IL-2, and MIP-1β levels decreased with disease progression.
Conclusions:
- Alterations in T-cell coreceptors and immune proteins occur across different HIV clades and disease stages.
- These observed changes do not appear to fully account for the differing disease progression rates between HIV clades A and D.
- The findings contribute to understanding the natural progression of non-clade B HIV infection and viral adaptation strategies.
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.
