title: Gastrointestinal-associated lymphoid tissue immune reconstitution in a randomized clinical trial of raltegravir versus non-nucleoside reverse transcriptase inhibitor-based regimens.
abstract: OBJECTIVE
  To examine immune restoration in duodenal tissue and correlates of reduction of immune activation in chronic HIV-infected patients randomized to different treatment regimens.
  
  
  METHODS
  Randomized clinical trial (RCT) comparing raltegravir to a non-nucleoside reverse transcriptase inhibitor-based regimen, both with fixed-dose tenofovir difumerate/emtricitabine.
  
  
  METHODS
  Antiretroviral therapy (ART)-naive volunteers underwent upper endoscopy for duodenal biopsies before and after 9 months of therapy. Tissue was paraffin-embedded for immunohistochemistry or digested into single-cell suspensions for flow cytometry of lymphocyte subsets and activation phenotype. Plasma-soluble CD14 levels were measured as a surrogate for bacterial translocation.
  
  
  RESULTS
  Sixteen HIV-positive and seven control individuals completed study procedures. Small increases in duodenal lamina propria CD4 T-cell numbers were observed, especially when viewed relative to populations in control volunteers, with no differences between treatment arms. The increase in CD4 T-cell percentage was due largely to declines in CD8 T-cell numbers, which were disproportionately increased compared to peripheral blood and controls. Patients randomized to the raltegravir arm had consistent declines in both sCD14 levels and CD8 T-cell numbers in the duodenal tissue lamina propria.
  
  
  CONCLUSIONS
  This first RCT of lymphocyte population restoration in duodenal tissue demonstrates more modest increases in CD4 T-cell numbers during the first 9 months of therapy than when considering CD3/CD4 percentages only. Although reduced after 9 months of ART, disproportional increased CD8 populations persist in duodenal gastrointestinal-associated lymphoid tissue (GALT). Local rather than systemic antigenic stimulation appears to be driving expanded CD8 T lymphocytes in GALT. Factors other than viral-induced CD8 expansion may be contributing to this local immunologic response.
authors: University of California Davis Medical School, Sacramento, CA 95817, USA. david.asmuth@ucdmc.ucdavis.edu
authors: David M
authors: DM
authors: Asmuth
authors: Zhong-Min
authors: ZM
authors: Ma
authors: Surinder
authors: S
authors: Mann
authors: Thomas H
authors: TH
authors: Knight
authors: Tammy
authors: T
authors: Yotter
authors: Anthony
authors: A
authors: Albanese
authors: Gregory P
authors: GP
authors: Melcher
authors: Paolo
authors: P
authors: Troia-Cancio
authors: Timothy
authors: T
authors: Hayes
authors: Chris J
authors: CJ
authors: Miller
authors: Richard B
authors: RB
authors: Pollard
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology*; D019380:Anti-HIV Agents / Q000276:immunology / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D004359:Drug Therapy, Combination; D004724:Endoscopy; D005260:Female; D041981:Gastrointestinal Tract / Q000276:immunology* / Q000473:pathology; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome / Q000139:chemically induced*; D007150:Immunohistochemistry; D008213:Lymphocyte Activation; D008221:Lymphoid Tissue / Q000276:immunology* / Q000473:pathology; D008297:Male; D019829:Nevirapine / Q000627:therapeutic use; D009570:Nitriles; D011724:Pyridazines / Q000627:therapeutic use; D011743:Pyrimidines; D011760:Pyrrolidinones / Q000627:therapeutic use*; D012367:RNA, Viral; D000068898:Raltegravir Potassium; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use; D019562:Viral Load
chemical_list: D019380:Anti-HIV Agents; D009570:Nitriles; D011724:Pyridazines; D011743:Pyrimidines; D011760:Pyrrolidinones; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; C451734:etravirine; D000068898:Raltegravir Potassium; D019829:Nevirapine