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

Abstract

IntroductionCombined 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.MethodsBiomarker 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.ResultsWe 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.ConclusionThese data provide evidence that blood sDPP4 levels could be useful as a correlate for HIV‐induced intestinal damage.

Non-human Primate Determinants of Natural Killer Cells in Tissues at Steady-State and During Simian Immunodeficiency Virus Infection

“…These distinct NK cell tissue distributions were associated with CXCR3 expression, supporting its role as an inflammatory tissue homing marker for NK cells. The higher levels of the CXCR3 ligand (IP-10) in the intestine of the SIVmac-infected macaques as compared with those of the SIVagm-infected AGMs (75,76) might explain in part, together with previously reported upregulations of other receptors such as α 4 β 7 , the higher levels of NK cells in the intestine of the SIVmac-infected macaques as compared with the natural host. The fact that NK cells seem to be redirected to the intestine in SIVmac infection raises the question of their inefficient activity against the cells replicating the virus in the gut.…”

Plasma levels of DPP4 activity and sDPP4 are dissociated from inflammation in mice and humans

“…Although sDPP4 directly induces inflammation in cells and animals 11,15,53 , whether circulating sDPP4 levels reflect the extent of localised or tissue inflammation is unclear. Levels of sDPP4 were reduced in humans with acute HIV infection and did not change with prolonged antiretroviral therapy 54 . In contrast, multiple studies demonstrated elevated levels of DPP4 activity and sDPP4 in subjects with obesity and/or T2D 11,15,39 , associated in some analyses with increased sDPP4 expression in circulating T cells 39 sDPP4 and liver enzymes in subjects with T2D, however levels of sDPP4 also decreased in the control group independent of changes in liver enzymes 55 .…”

The microbial metabolite trimethylamine-N-oxide in association with inflammation and microbial dysregulation in three HIV cohorts at various disease stages

“…Notably, levels of the soluble form, sDDP4, were decreased in primary and suppressed HIV-1 infection. Further, IL-21 treatment in a nonhuman primate model restored circulating sDPP4 levels and this increase was associated with restoration of the Th17 cell compartment and reduced inflammation in the gut mucosa (143), thus suggesting that circulating sDPP4 could be used as a surrogate marker for HIV-induced intestinal damage.…”