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

Informazioni relative al progetto

GLUTORHIV

ID dell’accordo di sovvenzione: 706871

DOI

10.3030/706871

Progetto chiuso

Data della firma CE 16 Marzo 2016

Data di avvio 1 Aprile 2016

Data di completamento 31 Marzo 2018

Finanziato da

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Costo totale

€ 185 076,00

Contributo UE

€ 185 076,00

Coordinato da

INSTITUT PASTEUR
France

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

Periodo di rendicontazione: 2016-04-01 al 2018-03-31

Sintesi del contesto e degli obiettivi generali del progetto

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.

Lavoro eseguito dall’inizio del progetto fino alla fine del periodo coperto dalla relazione e principali risultati finora ottenuti

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.

Progressi oltre lo stato dell’arte e potenziale impatto previsto (incluso l’impatto socioeconomico e le implicazioni sociali più ampie del progetto fino ad ora)

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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