Glucose metabolism and mTOR pathway role in CD8+ T.. (GLUTORHIV)
Glucose metabolism and mTOR pathway role in CD8+ T cell control of HIV-1
Start date: Apr 1, 2016,
End date: Mar 31, 2018
Antiretroviral therapy can decrease HIV-1 below the limit of detection but fails to eliminate the virus completely. One of the main goals of a HIV-1 vaccine is the generation of cytotoxic CD8 T cell responses that counteract the virus. CD8 T cells participate in the control of viremia early but progressively show weakened functions, which leads to loss of virus control. HIV controllers are a rare group of infected patients who can control the virus for years without antiretroviral therapy. CD8 T cells from HIV-controllers display an outstanding capacity to eliminate infected CD4 T cells ex vivo but the underlying mechanisms are still not understood.Preliminary data aiming at establishing a single cell transcriptional signature associated with control of HIV suggest an important role of the mTOR pathway during the chronic stage. This pathway plays a major role in glucose metabolism and CD8 T cells cytotoxic function. This raises the hypothesis that the extraordinary HIV-suppressive capacity of HIV-controllers CD8 T cells is associated with the modulation of mTOR pathway and glucose metabolism.This project aims to 1) Study the single cell gene expression of HIV-specific CD8 T cells in HIV patients longitudinally from acute to chronic stages and understand the factors linked to control and loss of function of CD8 T cells during disease progression. 2) To characterize the role of mTOR pathway in the ability of CD8 T cells from HIV-controller to eliminate infected cells and test if this pathway can be modulated to fine-tune anti-HIV CD8 T cells responses. 3) To understand if an optimal glucose metabolism is necessary for CD8 T-cells suppression of HIV and if this capacity can be improved by increasing available glucose. This work will help to understand the characteristics of effective CD8+ T cell responses against HIV and may guide the development of anti-HIV vaccines or immunotherapies to induce HIV controller-like responses in HIV-infected progressors.
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