title: Impaired T-cell proliferation among HAART-treated adults with suboptimal CD4 recovery in an African cohort.
abstract: BACKGROUND
  Most HIV-infected subjects exhibit a progressive rise in CD4 T-cell counts after initiation of highly active antiretroviral therapy (HAART). However, a subset of individuals exhibit very poor CD4 T-cell recovery despite effective control of HIV-RNA viraemia. We evaluated CD4 T-cell proliferation among suboptimal responders and its correlation with CD4 T-cell activation.
  
  
  METHODS
  The magnitude of CD4 increase (difference between absolute CD4 counts at baseline and absolute CD4 counts at 4 years of ART) was grouped into 4 quartiles for the 211 patients with sustained HIV-RNA viral suppression. Cases of 'Suboptimal immune responders' included patients within the lowest quartile [Median CD4 increase 165 (Range -43-298) cells/μl; n=52] and a comparison group of 'Optimal immune responders' was defined as patients within the highest quartile of CD4 increase [Median CD4 increase 528 (Range 417-878) cells/μl; n=52]. Frozen PBMC were thawed and analysed from a convenient sample of 39 suboptimal responders and 48 optimal responders after 4 years of suppressive antiretroviral therapy. T-cell activation was measured by proportions of T-cells expressing surface marker CD38 and HLADR (CD4+CD38+HLA-DR+ and CD8+CD38+HLA-DR+ cells). T-cell proliferation was determined by the extent of carboxyfluorescein diacetate succinimidyl ester (CFSE) dye dilution on culture day 5 of PBMCs in the presence of antigen (SEB, PPD, CMVpp65, GagA and GagD). Samples were analyzed on a FACS Calibur flow cytometer and flow data was analyzed using FlowJo and GraphPad.
  
  
  RESULTS
  Overall, CD4 T-cell proliferation on stimulation with SEB, PPD, CMVpp65, Gag A and Gag D.antigens, was lower among suboptimal than optimal responders; this was significant for SEB (CD4+ p=0.003; CD8+ p=0.048) and PPD antigens (CD8+ p=0.038). Among suboptimal responders, T-cell proliferation decreased with increasing immune activation (Negative correlation; slope = -0.13±-0.11) but not among optimal responders.
  
  
  CONCLUSIONS
  T-cell immune activation and exhaustion were associated with poor proliferation among suboptimal responders to HAART despite sustained viral suppression. We recommend studies to further understand the mechanisms leading to impaired T-cell function among suboptimal responders as well as the potential role of immune modulation in optimizing CD4 count and functional recovery after HAART.
authors.affiliation: Makerere University College of Health Sciences, Kampala, Uganda. drdamalie@yahoo.com
authors.forename: Damalie
authors.initials: D
authors.lastname: Nakanjako
authors.forename: Isaac
authors.initials: I
authors.lastname: Ssewanyana
authors.forename: Rose
authors.initials: R
authors.lastname: Nabatanzi
authors.forename: Agnes
authors.initials: A
authors.lastname: Kiragga
authors.forename: Moses R
authors.initials: MR
authors.lastname: Kamya
authors.forename: Huyen
authors.initials: H
authors.lastname: Cao
authors.forename: Harriet
authors.initials: H
authors.lastname: Mayanja-Kizza
mesh_terms: D000328:Adult; D000941:Antigens / Q000276:immunology; D023241:Antiretroviral Therapy, Highly Active; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology* / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology* / Q000821:virology; D049109:Cell Proliferation; D015331:Cohort Studies; D003710:Demography; D005260:Female; D005452:Fluoresceins / Q000378:metabolism; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology* / Q000821:virology; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D013388:Succinimides / Q000378:metabolism; D014454:Uganda
chemical_list: C087165:5-(6)-carboxyfluorescein diacetate succinimidyl ester; D000941:Antigens; D005452:Fluoresceins; D013388:Succinimides