Date Published: January 30, 2014
Publisher: Public Library of Science
Author(s): Irini Sereti, Jacob D. Estes, William L. Thompson, David R. Morcock, Margaret A. Fischl, Thérèse Croughs, Stéphanie Beq, Sylvie Lafaye de Micheaux, Michael D. Yao, Alexander Ober, Eleanor M. P. Wilson, Ven Natarajan, Hiromi Imamichi, Mohamed R. Boulassel, Michael M. Lederman, Jean-Pierre Routy, Guido Silvestri.
Despite antiretroviral therapy (ART), some HIV-infected persons maintain lower than normal CD4+ T-cell counts in peripheral blood and in the gut mucosa. This incomplete immune restoration is associated with higher levels of immune activation manifested by high systemic levels of biomarkers, including sCD14 and D-dimer, that are independent predictors of morbidity and mortality in HIV infection. In this 12-week, single-arm, open-label study, we tested the efficacy of IL-7 adjunctive therapy on T-cell reconstitution in peripheral blood and gut mucosa in 23 ART suppressed HIV-infected patients with incomplete CD4+ T-cell recovery, using one cycle (consisting of three subcutaneous injections) of recombinant human IL-7 (r-hIL-7) at 20 µg/kg. IL-7 administration led to increases of both CD4+ and CD8+ T-cells in peripheral blood, and importantly an expansion of T-cells expressing the gut homing integrin α4β7. Participants who underwent rectosigmoid biopsies at study baseline and after treatment had T-cell increases in the gut mucosa measured by both flow cytometry and immunohistochemistry. IL-7 therapy also resulted in apparent improvement in gut barrier integrity as measured by decreased neutrophil infiltration in the rectosigmoid lamina propria 12 weeks after IL-7 administration. This was also accompanied by decreased TNF and increased FOXP3 expression in the lamina propria. Plasma levels of sCD14 and D-dimer, indicative of systemic inflammation, decreased after r-hIL-7. Increases of colonic mucosal T-cells correlated strongly with the decreased systemic levels of sCD14, the LPS coreceptor – a marker of monocyte activation. Furthermore, the proportion of inflammatory monocytes expressing CCR2 was decreased, as was the basal IL-1β production of peripheral blood monocytes. These data suggest that administration of r-hIL-7 improves the gut mucosal abnormalities of chronic HIV infection and attenuates the systemic inflammatory and coagulation abnormalities that have been linked to it.
Mucosal CD4+ T-cell depletion in the gut is a hallmark of HIV pathogenesis . CD4+ T-cells residing in the gut mucosa are predominantly of memory phenotype and are frequently activated due to constant antigenic exposure. They typically express CCR5, the major HIV co-receptor, and α4β7, an integrin that assists gut homing of T-cells and can also facilitate HIV transmission , . The CD4+ T-cell depletion in the gut has been implicated in the pathogenesis and persistence of immune activation in untreated and chronically treated HIV infection , . The loss of epithelial integrity that accompanies the CD4+ T-cell loss leads to continuous activation of the innate system. Evidence of increased microbial translocation as reflected by increased systemic levels of bacterial lipopolysaccharide (LPS) or 16S DNA ,  has not been directly linked to clinical events in HIV infected patients treated with antiretroviral therapy (ART). On the other hand, biomarkers associated with monocyte activation (sCD14) as well as inflammation (IL-6) and coagulation (D-dimer) have been consistently found to be independent predictors of morbidity and mortality in this patient population –. Administration of ART can repair to a significant degree the HIV-inflicted gut mucosal injury ,  but studies suggest that CD4+ T-cells in the lamina propria (LP) may not be fully restored to the levels observed in uninfected controls. Recent evidence also suggests that defective T-cell trafficking, regulated by chemokines and their respective receptors, may be responsible for the altered T-cell homeostasis in the gut mucosa of HIV-infected persons after ART , .
In this study, the effects of in vivo administration of r-hIL-7 on the colonic mucosa were evaluated. Peripheral blood T-cell expansions were observed as previously reported , including an expansion of T-cells expressing the gut homing integrin α4β7. Rectosigmoid biopsies showed that peripheral T-cell expansions were accompanied by T-cell increases in the colonic mucosa. Importantly, we also observed a decrease in lamina propria neutrophil infiltration and TNF staining as well as a decrease in plasma levels of sCD14 and D-dimer, biomarkers that have been linked to morbidity and mortality in HIV infection. These findings suggest a potential role for r-hIL-7 in restoring mucosal integrity and decreasing local and systemic inflammation in patients with HIV infection on ART.