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

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

doi:10.1172/JCI130597

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

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. RobbNelson L. Michael, Mark De Souza, Nittaya Phanuphak, Jintanat Ananworanich, Lydie Trautmann^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

19 Scopus citations

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.

Original language	English
Pages (from-to)	2845-2858
Number of pages	14
Journal	Journal of Clinical Investigation
Volume	130
Issue number	6
DOIs	https://doi.org/10.1172/JCI130597
State	Published - 1 Jun 2020
Externally published	Yes

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Mitchell, J. L., Takata, H., Muir, R., Colby, D. J., Kroon, E., Crowell, T. A., Sacdalan, C., Pinyakorn, S., Puttamaswin, S., Benjapornpong, K., Trichavaroj, R., Tressler, R. L., Fox, L., Polonis, V. R., Bolton, D. L., Maldarelli, F., Lewin, S. R., Haddad, E. K., Phanuphak, P., ... Trautmann, L. (2020). Plasmacytoid dendritic cells sense HIV replication before detectable viremia following treatment interruption. Journal of Clinical Investigation, 130(6), 2845-2858. https://doi.org/10.1172/JCI130597

@article{3028da9d62b54a25aae75d654653c9f2,

title = "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.",

author = "Mitchell, {Julie L.} and Hiroshi Takata and Roshell Muir and Colby, {Donn J.} and Eug{\`e}ne Kroon and Crowell, {Trevor A.} and Carlo Sacdalan and Suteeraporn Pinyakorn and Suwanna Puttamaswin and Khunthalee Benjapornpong and Rapee Trichavaroj and Tressler, {Randall L.} and Lawrence Fox and Polonis, {Victoria R.} and Bolton, {Diane L.} and Frank Maldarelli and Lewin, {Sharon R.} and Haddad, {Elias K.} and Praphan Phanuphak and Robb, {Merlin L.} and Michael, {Nelson L.} and {De Souza}, Mark and Nittaya Phanuphak and Jintanat Ananworanich and Lydie Trautmann",

note = "Funding Information: We thank our study participants and staff at the TRC-ARC, Chu-lalongkorn University, and the AFRIMS for their valuable contributions to this study. We wish to thank M. Creegan for sorting samples. We are grateful to the Thai Government Pharmaceutical Organization, Gilead, Merck and ViiV Healthcare for providing antiretroviral agents for these studies. This study was supported by the NIH (R01AI108433 and R01MH106466) and a cooperative agreement (W81XWH-07-2-0067 and W81XWH-11-2-0174) between the HJF and the US Department of Defense. The views expressed are those of the authors and should not be construed to represent the positions of the US Army, the Department of Defense, the NIH, the Department of Health and Human Services, or HJF. See Supplemental Acknowledgments for details on the RV397, RV411, RV409, and RV254 study groups. Publisher Copyright: {\textcopyright} 2020, American Society for Clinical Investigation.",

year = "2020",

month = jun,

day = "1",

doi = "10.1172/JCI130597",

language = "English",

volume = "130",

pages = "2845--2858",

journal = "Journal of Clinical Investigation",

issn = "0021-9738",

number = "6",

}

Mitchell, JL, Takata, H, Muir, R, Colby, DJ, Kroon, E, Crowell, TA, Sacdalan, C, Pinyakorn, S, Puttamaswin, S, Benjapornpong, K, Trichavaroj, R, Tressler, RL, Fox, L, Polonis, VR, Bolton, DL, Maldarelli, F, Lewin, SR, Haddad, EK, Phanuphak, P, Robb, ML, Michael, NL, De Souza, M, Phanuphak, N, Ananworanich, J & Trautmann, L 2020, 'Plasmacytoid dendritic cells sense HIV replication before detectable viremia following treatment interruption', Journal of Clinical Investigation, vol. 130, no. 6, pp. 2845-2858. https://doi.org/10.1172/JCI130597

TY - JOUR

T1 - Plasmacytoid dendritic cells sense HIV replication before detectable viremia following treatment interruption

AU - Mitchell, Julie L.

AU - Takata, Hiroshi

AU - Muir, Roshell

AU - Colby, Donn J.

AU - Kroon, Eugène

AU - Crowell, Trevor A.

AU - Sacdalan, Carlo

AU - Pinyakorn, Suteeraporn

AU - Puttamaswin, Suwanna

AU - Benjapornpong, Khunthalee

AU - Trichavaroj, Rapee

AU - Tressler, Randall L.

AU - Fox, Lawrence

AU - Polonis, Victoria R.

AU - Bolton, Diane L.

AU - Maldarelli, Frank

AU - Lewin, Sharon R.

AU - Haddad, Elias K.

AU - Phanuphak, Praphan

AU - Robb, Merlin L.

AU - Michael, Nelson L.

AU - De Souza, Mark

AU - Phanuphak, Nittaya

AU - Ananworanich, Jintanat

AU - Trautmann, Lydie

N1 - Funding Information: We thank our study participants and staff at the TRC-ARC, Chu-lalongkorn University, and the AFRIMS for their valuable contributions to this study. We wish to thank M. Creegan for sorting samples. We are grateful to the Thai Government Pharmaceutical Organization, Gilead, Merck and ViiV Healthcare for providing antiretroviral agents for these studies. This study was supported by the NIH (R01AI108433 and R01MH106466) and a cooperative agreement (W81XWH-07-2-0067 and W81XWH-11-2-0174) between the HJF and the US Department of Defense. The views expressed are those of the authors and should not be construed to represent the positions of the US Army, the Department of Defense, the NIH, the Department of Health and Human Services, or HJF. See Supplemental Acknowledgments for details on the RV397, RV411, RV409, and RV254 study groups. Publisher Copyright: © 2020, American Society for Clinical Investigation.

PY - 2020/6/1

Y1 - 2020/6/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85085905232&partnerID=8YFLogxK

U2 - 10.1172/JCI130597

DO - 10.1172/JCI130597

M3 - Article

C2 - 32017709

AN - SCOPUS:85085905232

SN - 0021-9738

VL - 130

SP - 2845

EP - 2858

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 6

ER -

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

Abstract

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