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Abstract
Defective survival pathways in memory T cells during HIV infection
Haddad E.1, Riou C.1, Yassin Diab B.1, Gagnon D.1, Vendette M.1, Boulassel R.2, Routy J.-P.2, Sekaly R.-P.1
1University of Montreal, Montreal, Canada, 2McGill University, Montreal, Canada
Introduction: We have previously demonstrated the significance of central memory T cells in HIV infection as these cells either do not mature and are short-lived or become dysfunctional. However, the mechanisms by which memory T cells are maintained and survive are unknown.
Methods: Using gene array, PowerBlot and Phosflow assays, we have identified novel pathways that are required for the generation and survival of memory T cells in healthy and HIV infected individuals.
Results: We showed that in central memory CD4 T cells, PIM2, CD27 and TOSO are up-regulated. These genes are associated with different survival programs. PIM2 promotes BAD phosphorylation, abrogating its pro-apoptotic function. CD27 activates NFkB survival pathway, while TOSO inhibits FAS-mediated death. These results suggest that the long-term maintenance of central memory T cells is mediated by 2 different mechanisms. The first one is death receptor mediated and the second one involves activation of intrinsic survival molecules. Since the memory pathways are significantly perturbed in HIV infection, we used the knowledge acquired from studying memory T cells in homeostatic conditions to better understand their functions during HIV infection. We have shown that the genomics of memory T cells during HIV infections are significantly different than those from healthy individuals. We showed that both the IL-7 and BAD pathways are defective during HIV infection. We observed a decrease in the levels of expression in IL-7R, PIM2 mRNA in central memory obtained from HIV infected individuals compared to normal subjects.
Conclusions: Results suggest defect in the IL-7 and PIM associated survival pathways in memory T cells leading to an ineffective immune response during HIV infection. These data would greatly enhance our understanding of the immune response associated with HIV viral replication and disease pathogenesis.
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