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Human immunodeficiency virus viremia induces plasmacytoid dendritic cell activation in vivo and diminished alpha interferon production in vitro.

Tilton JC, Manion MM, Luskin MR, Johnson AJ, Patamawenu AA, Hallahan CW, Cogliano-Shutta NA, Mican JM, Davey RT, Kottilil S, Lifson JD, Metcalf JA, Lempicki RA, Connors M

LIR, NIAID, NIH, Bldg. 10, Rm. 11B-09, 10 Center Dr., MSC 1876, Bethesda, MD 20892-1876, USA.

Human immunodeficiency virus type 1 (HIV-1) infection has been associated with perturbations of plasmacytoid dendritic cells (PDC), including diminished frequencies in the peripheral blood and reduced production of type I interferons (IFNs) in response to in vitro stimulation. However, recent data suggest a paradoxical increase in production of type 1 interferons in vivo in HIV-infected patients compared to uninfected controls. Using a flow cytometric assay to detect IFN-alpha-producing cells within unseparated peripheral blood mononuclear cells, we observed that short-term interruptions of antiretroviral therapy are sufficient to result in significantly reduced IFN-alpha production by PDC in vitro in response to CpG A ligands or inactivated HIV particles. The primary cause of diminished IFN-alpha production was reduced responsiveness of PDC to de novo stimulation, not diminished per cell IFN-alpha production or migration of cells to lymphoid organs. Real-time PCR analysis of purified PDC from patients prior to and during treatment interruptions revealed that active HIV-1 replication is associated with upregulation of type I IFN-stimulated gene expression. Treatment of hepatitis C virus-infected patients with IFN-alpha2b and ribavirin for hepatitis C virus infection resulted in a profound suppression of de novo IFN-alpha production in response to CpG A or inactivated HIV particles, similar to the response observed in HIV-infected patients. Together, these results suggest that diminished production of type I interferons in vitro by PDC from HIV-1-infected patients may not represent diminished interferon production in vivo. Rather, diminished function in vitro is likely a consequence of prior activation via type I interferons or HIV virions in vivo.

Published 26 March 2008 in J Virol, 82(8): 3997-4006.
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