Gastrointestinal-associated lymphoid tissue immune reconstitution in a randomized clinical trial of raltegravir versus non-nucleoside reverse transcriptase inhibitor-based regimens

David Asmuth, Zhong Min Ma, Surinder K Mann, Thomas H. Knight, Tammy Yotter, Anthony Albanese, Gregory P. Melcher, Paolo Troia-Cancio, Timothy Hayes, Chris J Miller, Richard B Pollard

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

Objectives: To examine immune restoration in duodenal tissue and correlates of reduction of immune activation in chronic HIV-infected patients randomized to different treatment regimens. Design: 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.

Original languageEnglish (US)
Pages (from-to)1625-1634
Number of pages10
JournalAIDS
Volume26
Issue number13
DOIs
StatePublished - Aug 24 2012

Keywords

  • gastrointestinal associated lymphoid tissue
  • HIV
  • immune reconstitution
  • immunohistochemistry
  • non-nucleoside reverse transcriptase inhibitor
  • raltegravir
  • randomized clinical trial
  • sCD14 plasma levels

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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