1. P121 Impact of the dynamics of plasmacytoid dendritic cells in the regulation of alpha interferons during primary infection of cynomolgus macaques by simian immunodeficiency virus
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Bruel, T., Demoulins, T., Kreutz, C., Dutrieux, J., Cosma, A., Corneau, A., Dupuy, S., Delache, B., Torres, C., Cheynier, R., Bosquet, N., Grand, R. Le, and Vaslin, B.
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DENDRITIC cells , *GENETIC regulation , *INTERFERONS , *MACAQUES , *SIMIAN immunodeficiency virus , *IMMUNE response , *IMMUNOSUPPRESSION , *CLINICAL trials - Abstract
Introduction: Interferon-α response is one the first innate immune response to HIV/SIV infections during primary infection but is associated with immune suppression, chronic immune activation and pathogenesis. Cell types involved in Interferon alpha production are poorly defined as pDC activation levels are, and reasons for which IFN-α are only transiently detected during acute primary infection, and re-appear in the late clinical AIDS phase are not known. Methods: Macaques were infected by SIVmac251 to further analyse the dynamics of pDC and IFN-α during primary infection. We performed a multi-parameter followup: quality and kinetic of IFN-alpha responses (mRNA levels by RT-QPCR, antiviral activity by MDBK/VSV assay, ELISA), define cell types involved in IFN-α production (9 colors flow cytometry), monitor plasmacytoid DCs (pDC) activation/IFN-α production, monitor different pDC precursor stages by flow cytometry, monitor virus loads. Results: Plasma viral loads peaked on day 10–11 p.i. to progressively reach a plateau on month 2–3. IFN-α plasma concentrations peaked on day 7–9 p.i. to become rapidly undetectable after day 14–17 p.i.. pDCs were the only cell type with detectable of IFN-α levels in peripheral lymph nodes (PLN) leukocytes. IFN-α mRNA levels correlated both to viral RNA loads and % of IFN-α positive pDCs, which reached transiently 1.82% ±1.52 positive cells on day 9 p.i.. In gut mucosa, IFN-α mRNA levels were also increased in some macaques in association with a raise of BDCA-2 mRNA levels. In PLN a much higher % of pDC transiently show increased expression of activation and apoptosis markers as CCR7, HLA-DR, CD40, CD86, CD95 (on day 9 p.i, 41±13% of pDCs were HLA-DRhighCCR7high and 95±2.93 % were CD95 positive). In parallel we observed an increase of pDC with precursor phenotype (CD123lowHLA-DRlow, 22%±14 on day 9 p.i.) which express Ki67+ in PLN. This subtype is reminiscent of cells normally present in the bone marrow at steady state which are not able to produce IFN-α in response to SIV in vitro. The proportion of these Ki67+ precursor pDC population circulating in blood correlated with decreased production of IFN-α by pDCs in response to SIV in vitro. Setpoint was associated with a return to baseline of IFN-α mRNA levels in lymphnodes and gut mucosa, and to lower although sustained activation of pDC in lymph nodes, with no detectable IFN-α positive pDCs. Conclusion: These data: 1/support that pDC are the main contributors, if not the only, to IFN-α production in response to SIVin this phase. 2/Strongly suggest that the replacement of strongly activated pDC prone to apoptosis by non-functional bone marrow derived early pDC precursors in PLN contribute to rapid decrease of IFN-α production in primary infection, and may contribute to transient decrease of pDC responsiveness to in vitrostimulation. 3/Sustained activation of the pDC pool at set point in the absence of detectable IFN-α expression suggest different threshold of virus loads or imflammation are responsible for differential pDC functions in the chronic compared to primary phase. [Copyright &y& Elsevier]
- Published
- 2012
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