HIV infection progressively leads to a profound immune deficiency, resulting from the loss and dysfunction of helper CD4 T lymphocytes. Abnormal activation of the immune system is thought to play a central role in the anergy and apoptosis of patients' CD4 T lymphocytes. The Unit studies the cellular and molecular mechanisms that cause these dysfunctions, with a focus on the investigation of two major cytokines: IL-2 controls the expansion of recently activated T cells and the maintenance of CD25+ T regulatory cells, whereas IL-7 regulates both the thymopoiesis and the homeostasis of peripheral T lymphocytes. We demonstrate that these two cytokines play a central role in the pathogenesis of HIV infection.

IL-2 and IL-7 signaling defects and T cell dysfunction in viremic HIV-infected patients.

IL-2 production is decreased in HIV-infected patients. Furthermore, we find that, although CD4 T lymphocytes express the IL-2R, they have impaired IL-2 responses. In addition, in CD4 T lymphocyte from HIV+ patients, expression of the IL-7R is close to normal, but its function is altered. Altogether, these defects reduce immune responses and alter the IL-7/ CD4 loop regulating CD4 T cell counts. The mechanisms behind these defects (alteration of the Jak/STAT signaling pathway) are under study.

Biochemical characterization of a new IL-2R signaling complex and of new forms of the IL-7R

We identified a new IL-2R functional complex comprising IL-2Rbeta homodimers, Jak1 and STAT5. We are also studying the role of new forms of the IL-7R regulating CD4 and CD8 IL-7 response. These studies should allow the molecular characterization of the IL-2 and IL-7 signal transduction defects found in HIV patients.

HIV Controller patients.

HIV Controllers are a unique group defined by a spontaneous control of HIV-1 replication for ten years or more in the absence of therapy (O. Lambotte and J.-F. Delfraissy). In these patients, we show that HIV-specific responses are characterized by a preserved central memory CD4+ T cell compartment with intact IL-2 secretion capacity and a non-detrimental T cell immune activation.

Therapeutic potential of IL-2 and IL-7

A clinical trial was conducted with a group of patients who, when receiving anti-retroviral therapy (ARV), showed adequate control of their viral load but a low CD4 count recovery. In these patients, IL-2 rapidly induced the appearance of CD4+/CD25+ T lymphocytes with some Treg characteristics. These lymphocytes are presently under molecular characterization (in collaboration with L. Rogge). Our preclinical studies also show that IL-7 treatment in patients receiving ARV should promote efficient CD4 T cell counts restoration.