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5th International AIDS Society Conference on HIV Pathogenesis and TreatmentCape Town - July 19 - 22, 2009 |
PD-1 INDUCED IL-10 PRODUCTION BY MONOCYTES IMPAIRS CD4 T-CELL ACTIVATION DURING HIV INFECTION
IAS Conf HIV Pathog Treat 2009 Jul 19-22;5th: Abstract No. MOAA205
E.A. Said
1, L. Trautmann1, F.P. Dupuy1, Y. Zhang1, Y. Shi1, D.C. Douek2, E. Haddad1, R.P. Sekaly1
1Montreal University - CHUM, Microbiology and Immunology, Montreal, Canada, 2NIH, Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, Washington, United States
BACKGROUND: PD-1 up-regulation on T-cells is associated with chronic viral infections such as LCMV and HIV. Moreover, blocking PD-1/PD-L1 interaction results in the clearance of chronic LCMV infection and improves T-cell responses during HIV infection. Furthermore, persistent LCMV infection results in the up-regulation of IL-10 production by antigen-presenting cells, leading to impaired T-cell responses. Blocking IL-10/IL-10-receptor interaction restores T-cell function and eliminates viral infection. Interestingly, IL-10 levels are up-regulated during HIV infection. Monocytes have been demonstrated to be the major producer of IL-10 in HIV-infected subjects.
METHODS: We measured the levels of PD-1 expressed on monocytes in HIV-infected non-treated donors (viremic) as compared to HAART-treated (aviremic) and healthy donors and we investigated the conditions that lead to PD-1 upregulation on monocytes. Moreover, we explored the link between PD-1 triggering on monocytes and IL-10 production that leads to T-cell dysfunction.
RESULTS: PD-1 is up-regulated on CD16- and CD16+ monocytes in viremic donors as compared to aviremic and healthy donors. PD-1 expression was up-regulated by exposing monocytes to TLR ligands from microbial origin and to inflammatory cytokines, which are up-regulated in the blood of HIV-infected donors. The triggering of PD-1 induced IL-10 production by monocytes as early as 6 hours following the stimulation. Moreover, triggering through PD-1 inhibits antigen-specific T-cell response. This inhibition is due to IL-10 secretion by monocytes since it was reversed when a blocking anti-IL-10 receptor was added. Moreover, the spontaneous production of IL-10 by monocytes from viremic patients is inhibited by blocking PD-1/PD-L1 interaction.
CONCLUSION: We demonstrate a mechanism by which microbial products and inflammatory cytokines, present at high levels in the blood of HIV-infected donors, lead to the up-regulation of PD-1 on monocytes during HIV infection. Triggering through PD-1 by its physiological ligand PD-L1 induces IL-10 production, by monocytes, which inhibits T-cell responses.
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2009-07-22
MOAA205
Oral Abstract Session: MOAA2 - Subversion of Immune Responses in HIV Infection
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