Systemic DPP4 activity is reduced during primary HIV-1 infection and is associated with intestinal RORC+ CD4+ cell levels: a surrogate marker candidate of HIV-induced intestinal damage

Mickaël J Ploquin, Armanda Casrouge, Yoann Madec, Nicolas Noël, Beatrice Jacquelin, Nicolas Huot, Darragh Duffy, Simon P Jochems, Luca Micci, Camille Lécuroux, Faroudy Boufassa, Thijs Booiman, Thalia Garcia-Tellez, Mathilde Ghislain, Roger Le Grand, Olivier Lambotte, Neeltje Kootstra, Laurence Meyer, Cecile Goujard, Mirko Paiardini, Matthew L Albert, Michaela Müller-Trutwin, Mickaël J Ploquin, Armanda Casrouge, Yoann Madec, Nicolas Noël, Beatrice Jacquelin, Nicolas Huot, Darragh Duffy, Simon P Jochems, Luca Micci, Camille Lécuroux, Faroudy Boufassa, Thijs Booiman, Thalia Garcia-Tellez, Mathilde Ghislain, Roger Le Grand, Olivier Lambotte, Neeltje Kootstra, Laurence Meyer, Cecile Goujard, Mirko Paiardini, Matthew L Albert, Michaela Müller-Trutwin

Abstract

Introduction: Combined anti-retroviral therapy (cART) transformed HIV-1 from a deadly disease into a chronic infection, but does not cure HIV infection. It also does not fully restore HIV-induced gut damage unless administered extremely early after infection. Additional biomarkers are needed to evaluate the capacity of therapies aimed at HIV remission/cure to restore HIV-induced intestinal immune damage and limit chronic inflammation. Herein, we aimed to identify a systemic surrogate marker whose levels would reflect gut immune damage such as intestinal Th17 cell loss starting from primary HIV-1 infection.

Methods: Biomarker discovery approaches were performed in four independent cohorts, covering HIV-1 primary and chronic infection in 496 naïve or cART-treated patients (Amsterdam cohort (ACS), ANRS PRIMO, COPANA and CODEX cohorts). The concentration and activity of soluble Dipeptidylpeptidase 4 (sDPP4) were quantified in the blood from these patients, including pre- and post-infection samples in the ACS cohort. For quantification of DPP4 in the gut, we utilized two non-human primate models, representing pathogenic (macaque) and non-pathogenic (African green monkey) SIV infection. Four gut compartments were analysed in each animal model (ileum, jejunum, colon and rectum) for quantification of DPP4, RORC and TBX21 gene expression in sorted CD4+ cells. To analyse if sDPP4 levels increase when Th17 cells were restored, we quantified sDPP4 in plasma from SIV-infected macaques treated with IL-21.

Results: We showed that sDPP4 levels were strongly decreased in primary HIV-1 infection. Strikingly, sDPP4 levels in primary HIV-1 infection predicted time to AIDS. They were not increased by cART in chronic HIV-1 infection (median 36 months on cART). In the gut of SIV-infected non-human primates, DPP4 mRNA was higher in CD4+ than CD4- leucocytes. DPP4 specifically correlated with RORC expression, a Th17 marker, in CD4+ cells from the intestine. We further demonstrated that sDPP4 activity levels were increased in animals treated with IL-21 and that this increase was associated with restoration of the Th17 compartment and reduced inflammation. Furthermore, DPP4 mRNA levels in small intestine CD4+ cells positively correlated with circulating DPP4 activity.

Conclusion: These data provide evidence that blood sDPP4 levels could be useful as a correlate for HIV-induced intestinal damage.

Keywords: HIV; SIV; Th17; biomarker; dipeptidylpeptidase; inflammation; intestine.

© 2018 The Authors. Journal of the International AIDS Society published by John Wiley & sons Ltd on behalf of the International AIDS Society.

Figures

Figure 1
Figure 1
Soluble DPP4 levels in blood over time during distinct phases of HIV‐1 infection. (a) Soluble DPP4 activity levels over time in patients from the Amsterdam cohort Study (ACS). Blood collected before HIV‐1 infection and at early time points post‐infection were analysed. (b). Soluble DPP4 activity levels in 11 of these patients from the ACS for whom samples at all four time points of the study were available. (c) Soluble DPP4 activity levels in healthy donors (HD), in HIV‐infected treatment‐naive patients at early time points of infection (primary infection, PHI and six months post‐PHI) from the ANRS CO6 cohort, in the chronic phase of infection (viremic patients (VIR)) from the ANRS COPANA cohort, and during controlled infection, either cART‐treated patients (cART) from the COPANA cohort and HIV controllers (HIC) from the ANRS CODEX cohort. (d‐f) Evolution of sDPP4 levels before and during cART in 40 patients from the ANRS COPANA cohort. The values from the same patient are connected through a line to show the individual evolution of the sDPP4 levels before and after cART initiation. (d) Pre‐ and post‐ART sDPP4 activity (UI/mL) in the 40 cART‐treated patients. Twenty of these patients had received Protease inhibitors (PI). (e) Pre‐ and post‐ART sDPP4 activity (UI/mL) in 20 NRTI‐based cART‐treated patients. (f) Pre‐ and post‐ART sDPP4 activity (UI/mL) in the 20 patients on cART with PI‐containing regimen. Pre‐inf. = before HIV‐1 infection; PHI =  primary HIV‐1 infection; M3 = three months post‐seroconversion; M6 = 6 months post‐seroconversion (panel a‐b in the ACS) or post‐PHI (panel C in the PRIMO cohort). For graphs a, b and c, the median +interquartile range are shown. For graphs a and c, the student t‐test was used. For graphs b, d, e and f, the Wilcoxon sign‐rank test for paired data was used. *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001.
Figure 2
Figure 2
Soluble blood DPP4 levels with regard to disease progression profiles. Soluble DPP4 levels were quantified during primary HIV‐1 infection in patients from the ANRS PRIMO cohort displaying distinct profiles of disease progression (SP, slow progressors; P, normal progressors; RP, rapid progressors; HD, healthy donors). (a) sDPP4 enzymatic activity per ml of blood. The median levels were 18.0 for HD, 4.4 for SP and P and 3.8 for RP. (b) Kaplan–Meier survival analysis of AIDS‐related death by sDPP4 levels measured six months after seroconversion (M6) (≤ or > to the median) in treatment‐naïve patients from the Amsterdam cohort. The dotted line corresponds to sDPP4 levels > median and the solid line to sDDP4 levels < median at M6. For graph a, the Wilcoxon non‐parametric test was used and for graph b the log‐rank test. The median and interquartile range is shown in graph a. **p < 0.01; ***p < 0.001; ****p < 0.0001.
Figure 3
Figure 3
DPP4 mRNA levels in the gut in pathogenic and non‐pathogenic SIV infection. (a,c,e) Four intestinal compartments (ileum, jejunum, colon, rectum) from five rhesus macaques and five AGM were studied at an early phase of infection (day 65 pi.). CD4+ leucocytes were enriched from the distinct sections of the intestine. The values for the small intestine (ileum, jejunum) and large intestine (rectum, colon) were pooled. For MAC, the available material was: jejunum, colon and rectum for five animals, ileum for three to five animals; For AGM, the available samples were: jejunum, colon and rectum for four to five animals, ileum for four to five animals). When the material was limited, we privileged the analyses of DPP4mRNA. (a) DPP4 mRNA levels in intestinal CD4+ cells. (b) DPP4 mRNA expression in CD4+ cells from the small intestine (jejunum) from the five MAC and five AGM plotted against plasma sDPP4 activity in blood from the same animals. (c) RORCmRNA levels in intestinal CD4+ cells. (d) RORCmRNA expression levels plotted against DPP4 mRNA in CD4+ cells from the small intestine. (e) TBX21 (t‐bet) mRNA levels in intestinal CD4+ cells. (f) TBX21 mRNA expression levels plotted against DPP4 mRNA in CD4+ cells from the small intestine. The correlations were statistically significant when the two species were pooled, but not within individual species. (b,d,f) Each circle represents the value of one tissue sample. Black (full circles): MAC; white (open circles): AGM. For graphs a, c and e the Wilcoxon non‐parametric test was used; for graphs b, d and f the Spearman non‐parametric correlation was used. The median and interquartile range are shown in graphs a, c and e. FC, fold change. *p <  0.05; **p < 0.01; ***p < 0.001.
Figure 4
Figure 4
sDPP4 dynamics in blood after IL‐21 immunotherapy of SIV‐infected macaques. (a) sDPP4 activity in blood was measured in a longitudinal analysis before initiation of IL‐21 therapy (week 2 p.i.), at the end of IL‐21 treatment (week 6 p.i.) and after IL‐21 treatment (Weeks 10, 18 and 23 p.i.). The ratio of pre‐ and post‐treatment sDPP4 levels are shown. (b and c) IL‐17+ and IL‐17+ IFN‐•+ cells were measured in rectal biopsies on week 4 and week 6. (b) Correlation between the percentage of intestinal IL‐17+ IFN‐•+ cells and the plasma sDPP4 activity (fold change from week 2 to week 10) (c) Correlation between the percentage of intestinal IL‐17+ cells and plasma sDPP4 activity (fold change from week 2 to week 10). (d‐f) Correlation between sDPP4 activity in blood (fold change between week 2 and 10) and levels of (d) Ki67+ CD4+ T cells in gut (e) blood IP‐10 levels (f) blood sCD14 and (g) blood LPS after IL‐21 therapy cessation at week 23 p.i. For graph a, the Wilcoxon non‐parametric test was used; for graphs b to g, the Spearman non‐parametric correlation. The median and interquartile range are shown in graph a. *p < 0.05; **p < 0.01. Six rhesus macaques infected with SIVmac and treated with IL‐21 and six rhesus control macaques infected with SIVmac were analysed. CTRL: control monkeys; +IL‐21: IL‐21‐treated monkeys.

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