Major Depletion of Plasmacytoid Dendritic Cells in HIV-2 Infection, an Attenuated Form of HIV Disease

Abstract

Plasmacytoid dendritic cells (pDC) provide an important link between innate and acquired immunity, mediating their action mainly through IFN-α production. pDC suppress HIV-1 replication, but there is increasing evidence suggesting they may also contribute to the increased levels of cell apoptosis and pan-immune activation associated with disease progression. Although having the same clinical spectrum, HIV-2 infection is characterized by a strikingly lower viremia and a much slower rate of CD4 decline and AIDS progression than HIV-1, irrespective of disease stage. We report here a similar marked reduction in circulating pDC levels in untreated HIV-1 and HIV-2 infections in association with CD4 depletion and T cell activation, in spite of the undetectable viremia found in the majority of HIV-2 patients. Moreover, the same overexpression of CD86 and PD-L1 on circulating pDC was found in both infections irrespective of disease stage or viremia status. Our observation that pDC depletion occurs in HIV-2 infected patients with undetectable viremia indicates that mechanisms other than direct viral infection determine the pDC depletion during persistent infections. However, viremia was associated with an impairment of IFN-α production on a per pDC basis upon TLR9 stimulation. These data support the possibility that diminished function in vitro may relate to prior activation by HIV virions in vivo, in agreement with our finding of higher expression levels of the IFN-α inducible gene, MxA, in HIV-1 than in HIV-2 individuals. Importantly, serum IFN-α levels were not elevated in HIV-2 infected individuals. In conclusion, our data in this unique natural model of “attenuated” HIV immunodeficiency contribute to the understanding of pDC biology in HIV/AIDS pathogenesis, showing that in the absence of detectable viremia a major depletion of circulating pDC in association with a relatively preserved IFN-α production does occur.

Innate immunity in acute HIV-1 infection

“…SIVsmm infection of sooty mangabeys and SIVagm infection of African green monkeys) immunodeficiency virus infections, IFN-1 production is down-regulated following acute infection in the non-pathogenic infections, whilst high levels of ISG expression are sustained into chronic infection in the pathogenic infections [51, 96–99]. Likewise in HIV-2 infection, which is typically associated with slower CD4 decline and disease progression than HIV-1 infection, ISG expression levels during chronic infection are lower than those in HIV-1 infection [100]. The mechanisms responsible for the differential regulation of immune activation in pathogenic and non-pathogenic primate immunodeficiency virus infections are unclear, but are of priority to understand.…”

Cell-Associated Viral Burden Provides Evidence of Ongoing Viral Replication in Aviremic HIV-2-Infected Patients

“…Peripheral blood mononuclear cells (PBMC) were isolated immediately after blood collection and characterized by flow cytometry as previously described (9).…”

Short-term HIV-1 treatment interruption is associated with dysregulated TLR-stimuli responsiveness

“…The suggest, in agreement with previous studies, that the expression of TLR9-induced IFN-α is affected by loss of pDCs numbers as well as a functional defect of pDCs. 11,[34][35][36] Taken together, our results suggest that, in addition to viral rebound and decline in CD4 + T cells, TI also contributes to dysregulation of innate immunity, including fluctuation of DC subsets and defective or hyperactivated TLR responsiveness in HIV-1-infected individuals. Since differences in the viral and immunological parameters studied here were independent of vaccination regime, we chose to consider all study subjects as one group.…”