TY - JOUR
T1 - Integrative analysis of immunological data to explore chronic immune T-Cell activation in successfully treated HIV patients
AU - Picat, Marie-Quitterie
AU - Pellegrin, Isabelle
AU - Bitard, Juliette
AU - Wittkop, Linda
AU - Proust-Lima, Cécile
AU - Liquet, Benoît
AU - Moreau, Jean-François
AU - Bonnet, Fabrice
AU - Blanco, Patrick
AU - Thiébaut, Rodolphe
AU - Cohort, ANRS CO3 Aquitaine
N1 - Copyright the Author(s) 2017. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.
PY - 2017/1/3
Y1 - 2017/1/3
N2 - ObjectivesTo unravel the complex relationships between cytomegalovirus-induced-, autoimmune-induced responses, microbial translocation and chronic immune activation (CIA) in successfully treated HIV-infected patients and to explore the mediating role of alpha-interferon in these processes. DesignCross-sectional study nested in the ANRS CO3 Aquitaine Cohort, a prospective hospital-based cohort of HIV-1-infected patients in South-Western France. MethodsPatients initiated antiretroviral therapy between 2005 and 2008 and were treated with sustained virological suppression for at least two years. CIA was defined by the percentage of HLA-DR+/CD38+ among CD8+T-cells. Integrative analyses were performed using structural equation modelling (SEM). ResultsThe main analysis was performed in 57 HLA-A∗0201 positive patients, due to availability of percentages of actin-, vimentin-, lamin-specific CD8+T-cells (HLA-A2-restricted tests) to further characterize autoimmune response. Cytomegalovirus-induced response was assessed by Quantiferon and pp-65 ELISPOT. SEM revealed a direct effect of cytomegalovirus-induced response on CIA (standardized estimate βstd = 0.56, p-value = 0.0004). The effect of autoimmune-induced response on CIA was indirect through alpha-interferon pathway, assessed by expression levels of 5 alpha-interferon-stimulated genes ADAR, ISG15, IFIT1, Mx1 and OAS1 (effect of autoimmune response on alpha-interferon: βstd = 0.36, p-value = 0.0401; effect of alpha-interferon on CIA: βstd = 0.39, p-value = 0.0044). There was no direct effect of autoimmune-induced response on CIA (p-value = 0.3169). Microbial translocation as measured by 16SrDNA and sCD14 in plasma was not associated with CIA. Results were consistent in 142 patients in whom cytomegalovirus and auto-immunity responses were measured by Quantiferon and anti-nuclear antibodies, respectively. All analyses performed in HLA-A∗0201 positive patients and in the overall population revealed a significant effect of IFN-α latent variable on CIA. ConclusionThe role of cytomegalovirus-induced response on CIA was confirmed as well as the involvement of alpha-interferon on CIA. The indirect effect of auto-immunity response on CIA revealed through the alpha-interferon pathway requires further investigation to confirm the potential role of auto-immunity for CIA in HIV-infected patients.
AB - ObjectivesTo unravel the complex relationships between cytomegalovirus-induced-, autoimmune-induced responses, microbial translocation and chronic immune activation (CIA) in successfully treated HIV-infected patients and to explore the mediating role of alpha-interferon in these processes. DesignCross-sectional study nested in the ANRS CO3 Aquitaine Cohort, a prospective hospital-based cohort of HIV-1-infected patients in South-Western France. MethodsPatients initiated antiretroviral therapy between 2005 and 2008 and were treated with sustained virological suppression for at least two years. CIA was defined by the percentage of HLA-DR+/CD38+ among CD8+T-cells. Integrative analyses were performed using structural equation modelling (SEM). ResultsThe main analysis was performed in 57 HLA-A∗0201 positive patients, due to availability of percentages of actin-, vimentin-, lamin-specific CD8+T-cells (HLA-A2-restricted tests) to further characterize autoimmune response. Cytomegalovirus-induced response was assessed by Quantiferon and pp-65 ELISPOT. SEM revealed a direct effect of cytomegalovirus-induced response on CIA (standardized estimate βstd = 0.56, p-value = 0.0004). The effect of autoimmune-induced response on CIA was indirect through alpha-interferon pathway, assessed by expression levels of 5 alpha-interferon-stimulated genes ADAR, ISG15, IFIT1, Mx1 and OAS1 (effect of autoimmune response on alpha-interferon: βstd = 0.36, p-value = 0.0401; effect of alpha-interferon on CIA: βstd = 0.39, p-value = 0.0044). There was no direct effect of autoimmune-induced response on CIA (p-value = 0.3169). Microbial translocation as measured by 16SrDNA and sCD14 in plasma was not associated with CIA. Results were consistent in 142 patients in whom cytomegalovirus and auto-immunity responses were measured by Quantiferon and anti-nuclear antibodies, respectively. All analyses performed in HLA-A∗0201 positive patients and in the overall population revealed a significant effect of IFN-α latent variable on CIA. ConclusionThe role of cytomegalovirus-induced response on CIA was confirmed as well as the involvement of alpha-interferon on CIA. The indirect effect of auto-immunity response on CIA revealed through the alpha-interferon pathway requires further investigation to confirm the potential role of auto-immunity for CIA in HIV-infected patients.
UR - http://www.scopus.com/inward/record.url?scp=85008146954&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0169164
DO - 10.1371/journal.pone.0169164
M3 - Article
C2 - 28046052
SN - 1932-6203
VL - 12
SP - 1
EP - 19
JO - PLoS ONE
JF - PLoS ONE
IS - 1
M1 - e0169164
ER -