Plasmacytoid dendritic cells have divergent effects on HIV infection of initial target cells and induce a pro-retention phenotype

Abstract

Although HIV infection inhibits interferon responses in its target cells in vitro, interferon signatures can be detected in vivo soon after sexual transmission, mainly attributed to plasmacytoid dendritic cells (pDCs). In this study, we examined the physiological contributions of pDCs to early HIV acquisition using coculture models of pDCs with myeloid DCs, macrophages and the resting central, transitional and effector memory CD4 T cell subsets. pDCs impacted infection in a cell-specific manner. In myeloid cells, HIV infection was decreased via antiviral effects, cell maturation and downregulation of CCR5 expression. In contrast, in resting memory CD4 T cells, pDCs induced a subset-specific increase in intracellular HIV p24 protein expression without any activation or increase in CCR5 expression, as measured by flow cytometry. This increase was due to reactivation rather than enhanced viral spread, as blocking HIV entry via CCR5 did not alter the increased intracellular p24 expression. Furthermore, the load and proportion of cells expressing HIV DNA were restricted in the presence of pDCs while reverse transcriptase and p24 ELISA assays showed no increase in particle associated reverse transcriptase or extracellular p24 production. In addition, PDCs also markedly induced the expression of CD69 on infected CD4 T cells and other markers of CD4 T cell tissue retention. These phenotypic changes showed marked parallels with resident memory CD4 T cells isolated from anogenital tissue using enzymatic digestion. Production of IFNα by pDCs was the main driving factor for all these results. Thus, pDCs may reduce HIV spread during initial mucosal acquisition by inhibiting replication in myeloid cells while reactivating latent virus in resting memory CD4 T cells and retaining them for immune clearance.

Evolving Strategies to Eliminate the CD4 T Cells HIV Viral Reservoir via CAR T Cell Immunotherapy

“…Recently, a novel finding of HIV reactivation via IFN was reported (59) and showed that IFNa but no other IFN subtypes was able to efficiently reverse latency in both an in vitro model and in CD4 T cells collected from HIV patients on suppressive ART (59). This is similar to our recent findings of latency reversal in in vitro infected resting memory CD4 T cells (60) treated with IFNa8 or co-cultured with pDCs that secreted IFNa upon HIV exposure. Data from in vitro and humanized mice studies showed that IFNa8 and IFNa14 are more efficient at inhibiting HIV viral replication than IFNa2 (61) due to their higher affinities for the IFN receptor and the increased induction of antiviral proteins.…”

The HIV-1 proviral landscape reveals that Nef contributes to HIV-1 persistence in effector memory CD4+ T cells

“…Isolated CD4 + T cells (obtained as described below) were cultured at a concentration of 10 6 cells/ml in cRF10 (RPMI, Lonza) and 10% fetal bovine serum (RF10), supplemented with 1× GlutaMAX (Gibco), 100 U/ml penicillin (Gibco), and 100 μg/ml streptomycin (Gibco) in a 96-well U-bottom plate and incubated with the corresponding HIV-1 stock overnight at 37°C as previously described ( 84 ). Then, cells were washed 3 times with PBS, and cRF10 was added.…”

“…Isolation of memory CD4 + T cells to be infected with HIV-BaL and HIV-NL4-3-eGFP was performed as previously described ( 84 ).…”

The immunosuppressive Tuberculosis-associated microenvironment inhibits viral replication and promotes HIV-1 latency in CD4+ T cells

“…Based on our RNAseq data obtained from activated CD4+ T cells, we analyzed cellular pathways necessary for efficient HIV-1 transcription and viral reactivation of latently HIV-1infected cells (40)(41)(42)(43)(44)(45)(46)(47). These cellular pathways include the nuclear factor kappa-lightchain-enhancer of activated B cells (NF-B), Janus kinase/signal transducer and activator of transcription (JAK-STAT), tumor necrosis factor (TNF), extracellular signalregulated kinases (ERK) and type I/II interferon (IFN) pathways (40)(41)(42)(43)(44)(45)(46)(47). We found that NF-B, JAK-STAT and type I/II IFN pathways were downmodulated in activated cells treated with TB-PE (Figure 4A-B).…”