TY - JOUR
T1 - IL-17A reprograms intestinal epithelial cells to facilitate HIV-1 replication and outgrowth in CD4+ T cells
AU - Wiche Salinas, Tomas Raul
AU - Gosselin, Annie
AU - Raymond Marchand, Laurence
AU - Moreira Gabriel, Etiene
AU - Tastet, Olivier
AU - Goulet, Jean Philippe
AU - Zhang, Yuwei
AU - Vlad, Dragos
AU - Touil, Hanane
AU - Routy, Jean Pierre
AU - Bego, Mariana G.
AU - El-Far, Mohamed
AU - Chomont, Nicolas
AU - Landay, Alan L.
AU - Cohen, Éric A.
AU - Tremblay, Cécile
AU - Ancuta, Petronela
N1 - Funding Information:
This work was supported in part by funds from the Canadian Institutes of Health Research to PA (#MOP-114957; #TCO125276; IBC-154053), National Institutes of Health (NIH) to C.T. and P.A. (R01AG054324), as well as infrastructure funding from the Canadian Foundation for Innovation (CFI) to P.A. and C.T. Core facilities and human cohorts were supported by the Fondation du CHUM and the Fonds de recherche du Québec – Santé (FRQ-S) HIV/AIDS and Infectious Diseases Network. TWS was supported by Doctoral awards from the Université de Montréal and the FRQ-S. The authors thank Dr. Dana Gabuzda (Dana-Farber Cancer Institute, Boston, MA, USA) for providing the HIV NL4.3BAL molecular clone. Dr. Dominique Gauchat and Philippe St Onge (Flow Cytometry Core Facility, CHUM-Research Center, Montréal, QC, Canada) for expert technical support with polychromatic flow cytometry sorting; Olfa Debbeche (NLC3 Core Facility CHUM-Research Center, Montréal, QC, Canada); Mario Legault for his help with ethical approvals and informed consents; and Josée Girouard, Angie Massicotte, and Cynthia Dion, for their key contribution to study participant recruitment and access to blood samples and clinical information from HIV-infected and uninfected participants. The authors address a special thanks to all study participants for their key contribution to this work. T.R.W.S. contributed to the study design, performed all experiments, analyzed results, prepared figures, and wrote the manuscript. J.-P.G. and O.T. performed RNA-Seq analysis. O.T. contributed with figures from RNA-seq analysis. H.T. generated preliminary results for Figure 1A. A.G. Y.Z. L.R.M. E.M.G. and D.V. performed experiments. J.-P.R. and C.T. allowed access to biological samples and study participants clinical information. M.E.-F. N.C. and A.L.L. contributed to study design and provided protocols for IEC culture and HIV quantification. M.G.B. and E.A.C. kindly provided reagents and expertise for BST2 experiments. P.A. designed the study, contributed to data analysis and figure preparation, and wrote the manuscript. The authors declare no competing interests.
Funding Information:
This work was supported in part by funds from the Canadian Institutes of Health Research to PA ( #MOP-114957 ; #TCO125276 ; IBC-154053 ), National Institutes of Health ( NIH ) to C.T. and P.A. (R01AG054324), as well as infrastructure funding from the Canadian Foundation for Innovation ( CFI ) to P.A. and C.T. Core facilities and human cohorts were supported by the Fondation du CHUM and the Fonds de recherche du Québec – Santé (FRQ-S) HIV/AIDS and Infectious Diseases Network. TWS was supported by Doctoral awards from the Université de Montréal and the FRQ-S. The authors thank Dr. Dana Gabuzda (Dana-Farber Cancer Institute, Boston, MA, USA) for providing the HIV NL4.3BAL molecular clone. Dr. Dominique Gauchat and Philippe St Onge (Flow Cytometry Core Facility, CHUM-Research Center, Montréal, QC, Canada) for expert technical support with polychromatic flow cytometry sorting; Olfa Debbeche (NLC3 Core Facility CHUM-Research Center, Montréal, QC, Canada); Mario Legault for his help with ethical approvals and informed consents; and Josée Girouard, Angie Massicotte, and Cynthia Dion, for their key contribution to study participant recruitment and access to blood samples and clinical information from HIV-infected and uninfected participants. The authors address a special thanks to all study participants for their key contribution to this work.
Publisher Copyright:
© 2021
PY - 2021/11/19
Y1 - 2021/11/19
N2 - The crosstalk between intestinal epithelial cells (IECs) and Th17-polarized CD4+ T cells is critical for mucosal homeostasis, with HIV-1 causing significant alterations in people living with HIV (PLWH) despite antiretroviral therapy (ART). In a model of IEC and T cell co-cultures, we investigated the effects of IL-17A, the Th17 hallmark cytokine, on IEC ability to promote de novo HIV infection and viral reservoir reactivation. Our results demonstrate that IL-17A acts in synergy with TNF to boost IEC production of CCL20, a Th17-attractant chemokine, and promote HIV trans-infection of CD4+ T cells and viral outgrowth from reservoir cells of ART-treated PLWH. Importantly, the Illumina RNA-sequencing revealed an IL-17A-mediated pro-inflammatory and pro-viral molecular signature, including a decreased expression of type I interferon (IFN-I)-induced HIV restriction factors. These findings point to the deleterious features of IL-17A and raise awareness for caution when designing therapies aimed at restoring the paucity of mucosal Th17 cells in ART-treated PLWH.
AB - The crosstalk between intestinal epithelial cells (IECs) and Th17-polarized CD4+ T cells is critical for mucosal homeostasis, with HIV-1 causing significant alterations in people living with HIV (PLWH) despite antiretroviral therapy (ART). In a model of IEC and T cell co-cultures, we investigated the effects of IL-17A, the Th17 hallmark cytokine, on IEC ability to promote de novo HIV infection and viral reservoir reactivation. Our results demonstrate that IL-17A acts in synergy with TNF to boost IEC production of CCL20, a Th17-attractant chemokine, and promote HIV trans-infection of CD4+ T cells and viral outgrowth from reservoir cells of ART-treated PLWH. Importantly, the Illumina RNA-sequencing revealed an IL-17A-mediated pro-inflammatory and pro-viral molecular signature, including a decreased expression of type I interferon (IFN-I)-induced HIV restriction factors. These findings point to the deleterious features of IL-17A and raise awareness for caution when designing therapies aimed at restoring the paucity of mucosal Th17 cells in ART-treated PLWH.
KW - Immune response
KW - Immunology
KW - Virology
UR - http://www.scopus.com/inward/record.url?scp=85123060776&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85123060776&partnerID=8YFLogxK
U2 - 10.1016/j.isci.2021.103225
DO - 10.1016/j.isci.2021.103225
M3 - Article
C2 - 34712922
AN - SCOPUS:85123060776
SN - 2589-0042
VL - 24
JO - iScience
JF - iScience
IS - 11
M1 - 103225
ER -