Human immunodeficiency virus viremia induces plasmacytoid dendritic cell activation in vivo and diminished alpha interferon production in vitro.
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.
Tilton
John C
JC
LIR, NIAID, NIH, Bldg. 10, Rm. 11B-09, 10 Center Dr., MSC 1876, Bethesda, MD 20892-1876, USA.
Manion
Maura M
MM
Luskin
Marlise R
MR
Johnson
Alison J
AJ
Patamawenu
Andy A
AA
Hallahan
Claire W
CW
Cogliano-Shutta
Nancy A
NA
Mican
Joann M
JM
Davey
Richard T
RT
Kottilil
Shyam
S
Lifson
Jeffrey D
JD
Metcalf
Julia A
JA
Lempicki
Richard A
RA
Connors
Mark
M
D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology*; D005434:Flow Cytometry; D015658:HIV Infections / Q000150:complications / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006526:Hepatitis C / Q000188:drug therapy; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000096:biosynthesis* / Q000627:therapeutic use; D007963:Leukocytes, Mononuclear / Q000276:immunology; D011994:Recombinant Proteins; D012254:Ribavirin / Q000627:therapeutic use; D014766:Viremia / Q000276:immunology*
D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D012254:Ribavirin