Plasmacytoid dendritic cells sense HIV replication before detectable viremia following treatment interruption
Julie L. Mitchell, … , Lydie Trautmann, on behalf of the RV397, RV411, and RV254 Study Groups
Julie L. Mitchell, … , Lydie Trautmann, on behalf of the RV397, RV411, and RV254 Study Groups
Published February 4, 2020
Citation Information: J Clin Invest. 2020;130(6):2845-2858. https://doi.org/10.1172/JCI130597.
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Research Article AIDS/HIV Immunology

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

Abstract

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 transient decline in the ability of pDCs to produce IFNα in vitro, which correlated with decreased phosphorylation of IFN regulatory factory 7 (IRF7) and NF-κB. The levels of phosphorylated IRF7 and NF-κB inversely correlated with plasma IFNα2 levels, implying that pDCs were refractory to in vitro stimulation after IFNα 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.

Authors

Julie L. Mitchell, Hiroshi Takata, Roshell Muir, Donn J. Colby, Eugène Kroon, Trevor A. Crowell, Carlo Sacdalan, Suteeraporn Pinyakorn, Suwanna Puttamaswin, Khunthalee Benjapornpong, Rapee Trichavaroj, Randall L. Tressler, Lawrence Fox, Victoria R. Polonis, Diane L. Bolton, Frank Maldarelli, Sharon R. Lewin, Elias K. Haddad, Praphan Phanuphak, Merlin L. Robb, Nelson L. Michael, Mark de Souza, Nittaya Phanuphak, Jintanat Ananworanich, Lydie Trautmann, on behalf of the RV397, RV411, and RV254 Study Groups

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Figure 8

Schematic representation of pDC sensing of viral replication after ATI.

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Schematic representation of pDC sensing of viral replication after ATI. ...
Step 1: After interruption of antiretroviral therapy, viral recrudescence from HIV-infected CD4+ T cells occurs in the tissues. Step 2: Successful viral replication leads to the recruitment of innate immune cells, including pDCs, which are one of the first to respond to initial HIV infection. pDC sensing of virus at the site of recrudescence results in their activation and rapid cytokine production. Step 3: Production of CCL4 by activated pDCs can recruit more CD4+ T cells to the site of viral replication, resulting in further viral propagation and, eventually, measurable virus in the blood. Step 4: Our data demonstrate an increased frequency of pDCs in the blood prior to detection of plasma viremia after ATI. These pDCs expressed the activation markers CD69, PD-L1, and CD40 as well as increased levels of CXCR4 and CD29, suggesting that they were trafficking to sites of inflammation. Step 5: pDCs in the blood showed a transient decline in the ability to produce IFNα after stimulation in vitro, indicating that they enter a state of refraction after in vivo activation.