IL-23/IL-12 Imbalance and T Lymphocyte Polarization in HIV Infection
Condition: HIV Reservoirs
MeSH terms: HIV Infections
Study type: Interventional

Summary: 
      Progressive HIV or HIV infection seems to be related to a preferential loss of CD4+ T
      lymphocytes, especially Th17+, within the mucosal intestinal lymphoid tissue, and with
      intestinal mucosal damage and bacterial product translocation, which correlates with the
      hyperactivation of the immune system, therefore with CD4+ T cell loss and prognosis. The
      objectives of this project are to investigate the correlation between the IL12/IL-23
      imbalance and bacterial product translocation, and to study the polarization, infection or
      depletion of intestinal Th17 ex vivo. The investigators will test the effect of neutralizing
      anti-IL23 antibodies directed against p40, or less classically, anti- IL-23 p19.
    

Detailed description: 
      Th17 lymphocytes fight bacterial and fungal intestinal infections. Under combined
      antiretroviral therapy, even if the plasma viral load is undetectable, hyperactivation can
      persist, inducing localized replication from reservoirs. In humans, Th17 lymphocyte
      differentiation and expansion depend on IL-23. The investigators were the first to uncover an
      imbalance in the respective production of IL-12 and IL-23 in response to Lipopolysaccharide
      (LPS) in HIV-1 infected patients. IL-23 and its receptor are implicated in the pathogenesis
      of chronic inflammatory bowel diseases (IBD) like Crohn's disease, where the mucosa is
      altered by Th17 cells, inducing bacterial product translocation. IBD can be efficiently
      treated by antibodies directed against Tumor Necrosis Factor-α (TNF-α) or, in current
      clinical trials, against the p40 chain which is shared by IL-12 and IL-23. Unfortunately,
      these antibodies inhibit also IL-12. IL-12 is crucial against mycobacteria, which are
      opportunistic in HIV-infected patients. Antibodies directed against the p19 chain of IL-23
      would inhibit Th17 activation more specifically.

      The investigators will collect blood and recto-colic biopsies from 15 healthy donors, 15
      HIV-infected patients with a viral load higher than 5000 copies/ml and 15 patients with
      evolutive IBD, to establish a parallel between the two diseases.

      The objectives of this project are to study if there is a correlation between the IL12/IL-23
      imbalance and bacterial product translocation, and to investigate the polarization, infection
      or depletion of intestinal Th17 ex vivo. Investigators will test the effect of neutralizing
      anti-IL23 antibodies directed against p40, or less classically, anti- IL-23 p19.

      If these correlations are validated, the investigators will propose anti-IL-23 neutralizing
      treatment to allow Th17 and intestinal integrity to come back into balance, and therefore to
      break the vicious cycle of immune system hyperactivation drawn by bacterial translocation.
    

Intervention name(s): Blood sample and recto-colic biopsies
Intervention type(s): Other
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: HIV; Chronic inflammatory bowel disease; Reservoirs; IL-17; IL-23; Intestinal biopsies