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

PLoS One. 2014 May 9;9(5):e97011. doi: 10.1371/journal.pone.0097011. eCollection 2014.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Anti-Retroviral Agents / therapeutic use
  • CD4-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / immunology*
  • Cell Count
  • Cross-Sectional Studies
  • Female
  • Flow Cytometry
  • HIV Infections / drug therapy
  • HIV Infections / immunology*
  • Humans
  • Immunologic Memory / immunology*
  • L-Selectin / immunology
  • Leukocyte Common Antigens / immunology
  • Linear Models
  • Male
  • Middle Aged

Substances

  • Anti-Retroviral Agents
  • L-Selectin
  • Leukocyte Common Antigens

Grants and funding

Work was supported by an unrestricted fund from GlaxoSmithKline. http://www.gsk.ie/gsk_at_a_glance/glaxosmithkline_dublin.html. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.