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Plasmacytoid dendritic cells sense HIV replication before detectable viremia following treatment interruption.

ABSTRACT: Plasmacytoid dendritic cells (pDCs) are robust producers of IFN? and one of the first immune cells to respond to SIV infection. To elucidate responses to early HIV-1 replication, we studied blood pDCs in 29 HIV-infected participants who initiated antiretroviral therapy during acute infection and underwent analytic treatment interruption (ATI). We observed an increased frequency of partially activated pDCs in the blood before detection of HIV RNA. Concurrent with peak pDC frequency, we detected a transient decline in the ability of pDCs to produce IFN? in vitro, which correlated with decreased phosphorylation of IFN regulatory factory 7 (IRF7) and NF-?B. The levels of phosphorylated IRF7 and NF-?B inversely correlated with plasma IFN?2 levels, implying that pDCs were refractory to in vitro stimulation after IFN? production in vivo. After ATI, decreased expression of IFN genes in pDCs inversely correlated with the time to viral detection, suggesting that pDC IFN loss is part of an effective early immune response. These data from a limited cohort provide a critical first step in understanding the earliest immune response to HIV-1 and suggest that changes in blood pDC frequency and function can be used as an indicator of viral replication before detectable plasma viremia.

SUBMITTER: Mitchell JL

PROVIDER: S-EPMC7260031 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Plasmacytoid dendritic cells sense HIV replication before detectable viremia following treatment interruption.

Mitchell Julie L JL Takata Hiroshi H Muir Roshell R Colby Donn J DJ Kroon Eugène E Crowell Trevor A TA Sacdalan Carlo C Pinyakorn Suteeraporn S Puttamaswin Suwanna S Benjapornpong Khunthalee K Trichavaroj Rapee R Tressler Randall L RL Fox Lawrence L Polonis Victoria R VR Bolton Diane L DL Maldarelli Frank F Lewin Sharon R SR Haddad Elias K EK Phanuphak Praphan P Robb Merlin L ML Michael Nelson L NL de Souza Mark M Phanuphak Nittaya N Ananworanich Jintanat J Trautmann Lydie L

The Journal of clinical investigation 20200601 6

Plasmacytoid dendritic cells (pDCs) are robust producers of IFNα and one of the first immune cells to respond to SIV infection. To elucidate responses to early HIV-1 replication, we studied blood pDCs in 29 HIV-infected participants who initiated antiretroviral therapy during acute infection and underwent analytic treatment interruption (ATI). We observed an increased frequency of partially activated pDCs in the blood before detection of HIV RNA. Concurrent with peak pDC frequency, we detected a ...[more]

PMID: 32017709

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Project description:During antiretroviral therapy (ART) that suppresses HIV replication to below the limit-of-quantification, virions produced during ART can be detected at low frequencies in the plasma, termed residual viremia (RV). We hypothesized that a reservoir of HIV-infected cells actively produce and release virions during ART that are potentially infectious, and that following ART-interruption, these virions can complete full-cycles of replication and contribute to rebound viremia. Therefore, we studied the dynamics of RV sequence variants in 3 participants who initiated ART after ~3 years of infection and were ART-suppressed for >6 years prior to self-initiated ART-interruptions. Longitudinal RV C2V5env sequences were compared to sequences from pre-ART plasma, supernatants of quantitative viral outgrowth assays (QVOA) of cells collected during ART, post-ART-interruption plasma, and ART-re-suppression plasma. Identical, "putatively clonal," RV sequences comprised 8-84% of sequences from each timepoint. The majority of RV sequences were genetically similar to those from plasma collected just prior to ART-initiation, but as the duration of ART-suppression increased, an increasing proportion of RV variants were similar to sequences from earlier in infection. Identical sequences were detected in RV over a median of 3 years (range: 0.3-8.2) of ART-suppression. RV sequences were identical to pre-ART plasma viruses (5%), infectious viruses induced in QVOA (4%) and rebound viruses (5%) (total n = 21/154 (14%) across the 3 participants). RV sequences identical to ART-interruption "rebound" sequences were detected 0.1-7.4 years prior to ART-interruption. RV variant prevalence and persistence were not associated with detection of the variant among rebound sequences. Shortly after ART-re-suppression, variants that had been replicating during ART-interruptions were detected as RV (n = 5). These studies show a dynamic, virion-producing HIV reservoir that contributes to rekindling infection upon ART-interruption. The persistence of identical RV variants over years suggests that a subpopulation of HIV-infected clones frequently or continuously produce virions that may resist immune clearance; this suggests that cure strategies should target this active as well as latent reservoirs.

Dataset Information

Plasmacytoid dendritic cells sense HIV replication before detectable viremia following treatment interruption.

Publications

Plasmacytoid dendritic cells sense HIV replication before detectable viremia following treatment interruption.

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