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Julien van Grevenynghe
INRS-Institut Armand Frappier, Laval, Quebec, Canada
Posters & Accepted Abstracts: J Antivir Antiretrovir
The first months of HIV-1 infection are crucial for the establishment of the chronic phase of the infection and the disease progression. Indeed, the early infection is crucial for establishing the reservoirs and, thus, the chronic phase. The objective of this study is to analyse the underlying mechanisms responsible for reduced response of memory T-CD4 to IL-2 cytokine in early HIV infection involving deregulated metabolism. We demonstrate a clear correlation between the inflammation markers (sCD14, IL-6) of primary HIV-1-infected subjects (PHI) and the capacity of their T-CD4 to respond poorly to IL-2. This is validated by the lower level of induced phospho-STAT5 (pSTAT5) expression when compared to uninfected controls. Our results demonstrate that this impaired response to IL-2 results in the cell's inability to properly protect themselves from the Fasmediated cell death. Moreover, we demonstrate that the reduced response to IL-2 in memory CD4 T-cells from PHI directly involves the generation of reactive oxygen species (ROS). Interestingly, we also show that it is possible to partially restore the cytokine response in memory CD4 T-cells from PHI by treating the cells with n-acetyl cysteine (NAC), an antioxidant. We recently showed that kynurenines, derived from tryptophan metabolism, are clearly responsible for inhibiting IL-2 response through the oxidative stress. Finally, our study also reveals that the administration of early antiretroviral treatment leads to the restoration of IL-2 response in these subjects. Our study provides for the first time a link between the impaired memory T-CD4, the oxidative stress and kynurenine production during the first months of HIV-1 infection. This work is currently in submission in Journal of Clinical Investigation.