HIV Reservoirs Clinical Trial
Official title:
ANRS RF002 Intestipax : Interleukin-23 (IL-23)/Interleukin-12 (IL-12) Imbalance and T Lymphocyte Polarization in HIV Infection
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.
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.
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