Abstract
IFN-I production is a characteristic of HIV/SIV primary infections. However, acute IFN-I plasma concentrations rapidly decline thereafter. Plasmacytoid dendritic cells (pDC) are key players in this production but primary infection is associated with decreased responsiveness of pDC to TLR 7 and 9 triggering. IFNα production during primary SIV infection contrasts with increased pDC death, renewal and dysfunction. We investigated the contribution of pDC dynamics to both acute IFNα production and the rapid return of IFNα concentrations to pre-infection levels during acute-to-chronic transition. Nine cynomolgus macaques were infected with SIVmac251 and IFNα-producing cells were quantified and characterized. The plasma IFN-I peak was temporally associated with the presence of IFNα+ pDC in tissues but IFN-I production was not detectable during the acute-to-chronic transition despite persistent immune activation. No IFNα+ cells other than pDC were detected by intracellular staining. Blood-pDC and peripheral lymph node-pDC both lost IFNα− production ability in parallel. In blood, this phenomenon correlated with an increase in the counts of Ki67+-pDC precursors with no IFNα production ability. In tissues, it was associated with increase of both activated pDC and KI67+-pDC precursors, none of these being IFNα+ in vivo. Our findings also indicate that activation/death-driven pDC renewal rapidly blunts acute IFNα production in vivo: pDC sub-populations with no IFNα-production ability rapidly increase and shrinkage of IFNα production thus involves both early pDC exhaustion, and increase of pDC precursors.
Highlights
HIV-1 infection is characterized by chronic immune activation, a major cause of CD4 T-cell depletion and HIV/Simian immunodeficiency virus (SIV)-specific immunity dysfunction, and facilitating viral replication and progression to AIDS [1]
Using the cynomolgus macaque model of progressive SIV infection, we demonstrate in vivo that plasmacytoid dendritic cells are major contributors to IFNa production in lymphoid tissues and, most importantly, that this production rapidly shrinks after primary infection
We investigated the involvement of Plasmacytoid dendritic cells (pDC) in IFNa production in blood and tissues during the early stages of SIV infection in cynomolgus macaques (CyM) and studied the role of pDC sub-population dynamics in IFNa production
Summary
HIV-1 infection is characterized by chronic immune activation, a major cause of CD4 T-cell depletion and HIV/SIV-specific immunity dysfunction, and facilitating viral replication and progression to AIDS [1]. Simian immunodeficiency virus (SIV) infection in non human primates (NHP) leads to chronic immune activation and AIDS in macaques, but not in the natural African NHP hosts despite persistently high viremia [2]. Acute interferon-alpha (IFNa) production is observed in both lymphoid and non-lymphoid tissues during primary Simian Immunodeficiency Virus (SIV) infection (PSI) [6,7], but is barely detectable during the chronic stage of pathogenic HIV/SIV infection until the late symptomatic stage [4,8,9,10]. The cellular source of IFN-I and site of its activity during the early chronic phase remain elusive, and the mechanism leading to the reduction of IFNa production during the acute-to-chronic transition phase of HIV/SIV infections have not been rigorously described [11]
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