title: Clinical, immunological and treatment-related factors associated with normalised CD4+/CD8+ T-cell ratio: effect of naïve and memory T-cell subsets.
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.
authors.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.
authors.forename: Willard
authors.initials: W
authors.lastname: Tinago
authors.affiliation: HIV Molecular Research Group, School of Medicine and Medical Science, University College Dublin, Dublin, Ireland.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Coghlan
authors.affiliation: HIV Molecular Research Group, School of Medicine and Medical Science, University College Dublin, Dublin, Ireland.
authors.forename: Alan
authors.initials: A
authors.lastname: Macken
authors.affiliation: Department of Immunology, Mater Misericordiae University Hospital, Dublin, Ireland.
authors.forename: Julie
authors.initials: J
authors.lastname: McAndrews
authors.affiliation: Department of Immunology, Mater Misericordiae University Hospital, Dublin, Ireland.
authors.forename: Brenda
authors.initials: B
authors.lastname: Doak
authors.affiliation: Department of Immunology, Mater Misericordiae University Hospital, Dublin, Ireland.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Prior-Fuller
authors.affiliation: HIV Molecular Research Group, School of Medicine and Medical Science, University College Dublin, Dublin, Ireland; Department of Infectious Diseases, Mater Misericordiae University Hospital, Dublin, Ireland.
authors.forename: John S
authors.initials: JS
authors.lastname: Lambert
authors.affiliation: HIV Molecular Research Group, School of Medicine and Medical Science, University College Dublin, Dublin, Ireland; Department of Infectious Diseases, Mater Misericordiae University Hospital, Dublin, Ireland.
authors.forename: Gerard J
authors.initials: GJ
authors.lastname: Sheehan
authors.affiliation: HIV Molecular Research Group, School of Medicine and Medical Science, University College Dublin, Dublin, Ireland; Department of Infectious Diseases, Mater Misericordiae University Hospital, Dublin, Ireland.
authors.forename: Patrick W G
authors.initials: PW
authors.lastname: Mallon
mesh_terms: D000328:Adult; D044966:Anti-Retroviral Agents / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002452:Cell Count; D003430:Cross-Sectional Studies; D005260:Female; D005434:Flow Cytometry; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology*; D019041:L-Selectin / Q000276:immunology; D017493:Leukocyte Common Antigens / Q000276:immunology; D016014:Linear Models; D008297:Male; D008875:Middle Aged
chemical_list: D044966:Anti-Retroviral Agents; D019041:L-Selectin; D017493:Leukocyte Common Antigens