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Glucose metabolism and mTOR pathway role in CD8+ T cell control of HIV-1

Periodic Reporting for period 1 - GLUTORHIV (Glucose metabolism and mTOR pathway role in CD8+ T cell control of HIV-1)

Reporting period: 2016-04-01 to 2018-03-31

Antiretroviral therapy can decrease HIV-1 below the limit of detection but fails to eliminate the virus that remains in latent reservoirs. New strategies to better control the virus must be developed. The HIV-controllers (HIC) are a rare group of patients infected by HIV-1 who can control the virus below the limit of detection for years without antiretroviral therapy. Spontaneous control of HIV is generally associated with an enhanced capacity of CD8+ T cells to eliminate infected CD4+ T cells, but the molecular characteristics of these highly functional CD8+ T cells are largely unknown.

Based on our preliminary data, We made the hypothesis that the extraordinary HIV suppressive capacity of HIV-controllers CD8+ T cells during chronic infection might be associated with an optimal modulation of mTOR pathway (important for differentiation and function) and glucose metabolism (regulates activation, differentiation and functions) fueling those cells.
Our results show that the enhanced functionality of HIV-specific CD8 T cells from HIC is imprinted in their memory program and is associated to their ability to use diverse metabolic resources. In contrast, poor functionality of cells from non controllers is associated with dependency on glycolysis as primary energy source. Our data thus point to a metabolic profile compatible with better cell survival and a preserved potential to develop a higher quality anti-HIV effector functions in stressful conditions. The metabolic profile of CD8+ T cells from non-controllers can be enhanced in vitro, resulting in an increased capacity to kill HIV-infected CD4 T cells. Our study suggest that improving metabolic fitness of HIV-specific CD8+ T from cells via pharmacological tools could help to restore their function and lead to HIV remission in non controllers.

This work was presented as a poster in national (Sidaction Science Day) and international conferences (Keystone Symposium “Integrating Metabolism and Immunity”, International Pasteur Institute Network Conference) and also led to oral presentations in national conferences (Sidaction Science day, Institut Pasteur Virology Club) and one invited seminar (Pitie salpetriere Hospital).

The presentation of this work during the 2017 International AIDS Society conference was joined by a press release.
To our knowledge, this the first study to establish a direct link between HIV control and CD8+ T cell metabolism. This work could lead to the use pharmacological tools to enhance HIV-specific CD8+ T cells survival and effector function and help paving the way to new therapeutic strategies to induce HIV remission and to develop therapeutic vaccines. Achieving HIV remission could have a major impact of the quality of life of the individuals using these antiretroviral drugs that can induce deleterious side effects and are expensive (the estimated lifetime treatment cost of an HIV infection is $379,668). HIV remission could also change the view of society on HIV-infected individuals who face stigma and discrimination.
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