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Clinical, immunological and treatment-related factors associated with normalised CD4+/CD8+ T-cell ratio: effect of naïve and memory T-cell subsets.

Tinago W, Coghlan E, Macken A, McAndrews J, Doak B, Prior-Fuller C, Lambert JS, Sheehan GJ, Mallon PW, Mater Immunology Study Gro - PLoS ONE (2014)

Bottom Line: Of the CD8+ T-cells subsets, 16.5(10.2-25.5)% were naïve, 19.9(12.7-26.6)% central memory and 41.0(31.8-52.5)% effector memory.In the multivariable adjusted analysis, total cumulative-ART exposure(+0.15,p = 0.007), higher nadir CD4+ count(+0.011,p<0.001) and higher %CD8+ naive T-cells(+0.0085,p<0.001) were associated with higher CD4+/CD8+ ratio, higher absolute CD8+ T-cell(-0.0044,p<0.001) and higher %CD4+ effector memory T-cells(-0.004,p = 0.0036) were associated with lower CD4+/CD8+ ratio.Those with CD4+/CD8+ ratio>1 had significantly higher median %CD8+ naive T-cells; 25.4(14.0-36.0)% versus 14.4(9.4-21.6)%, p<0.0001, but significantly lower absolute CD8+ count; 464(384.5-567) versus 765(603-1084) cells/mm3, p<0.001.

View Article: PubMed Central - PubMed

Affiliation: HIV Molecular Research Group, School of Medicine and Medical Science, University College Dublin, Dublin, Ireland; Department of Community Medicine, University of Zimbabwe, Harare, Zimbabwe.

ABSTRACT

Background: Although effective antiretroviral therapy(ART) increases CD4+ T-cell count, responses to ART vary considerably and only a minority of patients normalise their CD4+/CD8+ ratio. Although retention of naïve CD4+ T-cells is thought to predict better immune responses, relationships between CD4+ and CD8+ T-cell subsets and CD4+/CD8+ ratio have not been well described.

Methods: A cross-sectional study in a cohort of ambulatory HIV+ patients. We used flow cytometry on fresh blood to determine expanded CD4+ and CD8+ T-cell subsets; CD45RO+CD62L+(central memory), CD45RO+CD62L-(effector memory) and CD45RO-CD62L+(naïve) alongside routine T-cell subsets(absolute, percentage CD4+ and CD8+ counts), HIVRNA and collected demographic and treatment data. Relationship between CD4+/CD8+ T-cell ratio and expanded T-cell subsets was determined using linear regression analysis. Results are median[IQR] and regression coefficients unless stated.

Results: We recruited 190 subjects, age 42(36-48) years, 65% male, 65.3% Caucasian, 91% on ART(52.6% on protease inhibitors), 78.4% with HIVRNA<40cps/ml and median ART duration 6.8(2.6-10.2) years. Nadir and current CD4+ counts were 200(112-309) and 465(335-607) cells/mm3 respectively. Median CD4+/CD8+ ratio was 0.6(0.4-1.0), with 26.3% of subjects achieving CD4+/CD8+ ratio>1. Of the expanded CD4+ T-cell subsets, 27.3(18.0-38.3)% were naïve, 36.8(29.0-40.0)% central memory and 27.4(20.0-38.5)% effector memory. Of the CD8+ T-cells subsets, 16.5(10.2-25.5)% were naïve, 19.9(12.7-26.6)% central memory and 41.0(31.8-52.5)% effector memory. In the multivariable adjusted analysis, total cumulative-ART exposure(+0.15,p = 0.007), higher nadir CD4+ count(+0.011,p<0.001) and higher %CD8+ naive T-cells(+0.0085,p<0.001) were associated with higher CD4+/CD8+ ratio, higher absolute CD8+ T-cell(-0.0044,p<0.001) and higher %CD4+ effector memory T-cells(-0.004,p = 0.0036) were associated with lower CD4+/CD8+ ratio. Those with CD4+/CD8+ ratio>1 had significantly higher median %CD8+ naive T-cells; 25.4(14.0-36.0)% versus 14.4(9.4-21.6)%, p<0.0001, but significantly lower absolute CD8+ count; 464(384.5-567) versus 765(603-1084) cells/mm3, p<0.001.

Conclusions: Study suggests important role for naïve CD8+ T-cell populations in normalisation of the immune response to HIV-infection. How these findings relate to persistent immune activation on ART requires further study.

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Related in: MedlinePlus

Correlation between CD4+ and CD8+ expanded T-cell subsets with CD4+/CD8, CD4+ and CD8+ T-cells.
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pone-0097011-g001: Correlation between CD4+ and CD8+ expanded T-cell subsets with CD4+/CD8, CD4+ and CD8+ T-cells.

Mentions: We further explored whether as a surrogate marker of immune response, the CD4+/CD8+ T-cell ratio is a better indicator of expanded T-cell subset, compared to CD4+ and CD8+ T-cell count. In the unadjusted analysis, the CD4+/CD8+ T-cell ratio showed the strongest association to %CD4+ effector memory T-cells (rho = −0.39, p<0.001), %CD8+ naive T-cells (rho = +0.41, p<0.001) and %CD8 effector memory T-cells (rho = −0.34, p<0.001), compared to CD4+ and CD8+ T-cell count (Figure 1). CD4+ T-cell count showed the strongest association to %CD4+ naïve T-cells (rho = +0.40, p<0.001) compared to the CD4+/CD8+ T-cell ratio and CD8+ T-cell count. CD8+ T-cell count showed the strongest association to %CD4+ central memory T-cells (rho = −0.22, p = 0.002) and %CD8 central memory T-cells (rho = −0.29, p<0.001). These crude associations rather suggest that CD4+/CD8+ T-cell ratio could be more informative on %CD4+ effector memory, %CD8+ naive and %CD8+ effector memory T-cells, while CD4+ T-cell count could be more informative on %CD4 naïve T-cells and CD8+ T-cell count on %CD8 central memory T-cells and %CD4+ central memory T-cells.


Clinical, immunological and treatment-related factors associated with normalised CD4+/CD8+ T-cell ratio: effect of naïve and memory T-cell subsets.

Tinago W, Coghlan E, Macken A, McAndrews J, Doak B, Prior-Fuller C, Lambert JS, Sheehan GJ, Mallon PW, Mater Immunology Study Gro - PLoS ONE (2014)

Correlation between CD4+ and CD8+ expanded T-cell subsets with CD4+/CD8, CD4+ and CD8+ T-cells.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4016205&req=5

pone-0097011-g001: Correlation between CD4+ and CD8+ expanded T-cell subsets with CD4+/CD8, CD4+ and CD8+ T-cells.
Mentions: We further explored whether as a surrogate marker of immune response, the CD4+/CD8+ T-cell ratio is a better indicator of expanded T-cell subset, compared to CD4+ and CD8+ T-cell count. In the unadjusted analysis, the CD4+/CD8+ T-cell ratio showed the strongest association to %CD4+ effector memory T-cells (rho = −0.39, p<0.001), %CD8+ naive T-cells (rho = +0.41, p<0.001) and %CD8 effector memory T-cells (rho = −0.34, p<0.001), compared to CD4+ and CD8+ T-cell count (Figure 1). CD4+ T-cell count showed the strongest association to %CD4+ naïve T-cells (rho = +0.40, p<0.001) compared to the CD4+/CD8+ T-cell ratio and CD8+ T-cell count. CD8+ T-cell count showed the strongest association to %CD4+ central memory T-cells (rho = −0.22, p = 0.002) and %CD8 central memory T-cells (rho = −0.29, p<0.001). These crude associations rather suggest that CD4+/CD8+ T-cell ratio could be more informative on %CD4+ effector memory, %CD8+ naive and %CD8+ effector memory T-cells, while CD4+ T-cell count could be more informative on %CD4 naïve T-cells and CD8+ T-cell count on %CD8 central memory T-cells and %CD4+ central memory T-cells.

Bottom Line: Of the CD8+ T-cells subsets, 16.5(10.2-25.5)% were naïve, 19.9(12.7-26.6)% central memory and 41.0(31.8-52.5)% effector memory.In the multivariable adjusted analysis, total cumulative-ART exposure(+0.15,p = 0.007), higher nadir CD4+ count(+0.011,p<0.001) and higher %CD8+ naive T-cells(+0.0085,p<0.001) were associated with higher CD4+/CD8+ ratio, higher absolute CD8+ T-cell(-0.0044,p<0.001) and higher %CD4+ effector memory T-cells(-0.004,p = 0.0036) were associated with lower CD4+/CD8+ ratio.Those with CD4+/CD8+ ratio>1 had significantly higher median %CD8+ naive T-cells; 25.4(14.0-36.0)% versus 14.4(9.4-21.6)%, p<0.0001, but significantly lower absolute CD8+ count; 464(384.5-567) versus 765(603-1084) cells/mm3, p<0.001.

View Article: PubMed Central - PubMed

Affiliation: HIV Molecular Research Group, School of Medicine and Medical Science, University College Dublin, Dublin, Ireland; Department of Community Medicine, University of Zimbabwe, Harare, Zimbabwe.

ABSTRACT

Background: Although effective antiretroviral therapy(ART) increases CD4+ T-cell count, responses to ART vary considerably and only a minority of patients normalise their CD4+/CD8+ ratio. Although retention of naïve CD4+ T-cells is thought to predict better immune responses, relationships between CD4+ and CD8+ T-cell subsets and CD4+/CD8+ ratio have not been well described.

Methods: A cross-sectional study in a cohort of ambulatory HIV+ patients. We used flow cytometry on fresh blood to determine expanded CD4+ and CD8+ T-cell subsets; CD45RO+CD62L+(central memory), CD45RO+CD62L-(effector memory) and CD45RO-CD62L+(naïve) alongside routine T-cell subsets(absolute, percentage CD4+ and CD8+ counts), HIVRNA and collected demographic and treatment data. Relationship between CD4+/CD8+ T-cell ratio and expanded T-cell subsets was determined using linear regression analysis. Results are median[IQR] and regression coefficients unless stated.

Results: We recruited 190 subjects, age 42(36-48) years, 65% male, 65.3% Caucasian, 91% on ART(52.6% on protease inhibitors), 78.4% with HIVRNA<40cps/ml and median ART duration 6.8(2.6-10.2) years. Nadir and current CD4+ counts were 200(112-309) and 465(335-607) cells/mm3 respectively. Median CD4+/CD8+ ratio was 0.6(0.4-1.0), with 26.3% of subjects achieving CD4+/CD8+ ratio>1. Of the expanded CD4+ T-cell subsets, 27.3(18.0-38.3)% were naïve, 36.8(29.0-40.0)% central memory and 27.4(20.0-38.5)% effector memory. Of the CD8+ T-cells subsets, 16.5(10.2-25.5)% were naïve, 19.9(12.7-26.6)% central memory and 41.0(31.8-52.5)% effector memory. In the multivariable adjusted analysis, total cumulative-ART exposure(+0.15,p = 0.007), higher nadir CD4+ count(+0.011,p<0.001) and higher %CD8+ naive T-cells(+0.0085,p<0.001) were associated with higher CD4+/CD8+ ratio, higher absolute CD8+ T-cell(-0.0044,p<0.001) and higher %CD4+ effector memory T-cells(-0.004,p = 0.0036) were associated with lower CD4+/CD8+ ratio. Those with CD4+/CD8+ ratio>1 had significantly higher median %CD8+ naive T-cells; 25.4(14.0-36.0)% versus 14.4(9.4-21.6)%, p<0.0001, but significantly lower absolute CD8+ count; 464(384.5-567) versus 765(603-1084) cells/mm3, p<0.001.

Conclusions: Study suggests important role for naïve CD8+ T-cell populations in normalisation of the immune response to HIV-infection. How these findings relate to persistent immune activation on ART requires further study.

Show MeSH
Related in: MedlinePlus