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Adipose Tissue Is a Neglected Viral Reservoir and an Inflammatory Site during Chronic HIV and SIV Infection.

Damouche A, Lazure T, Avettand-Fènoël V, Huot N, Dejucq-Rainsford N, Satie AP, Mélard A, David L, Gommet C, Ghosn J, Noel N, Pourcher G, Martinez V, Benoist S, Béréziat V, Cosma A, Favier B, Vaslin B, Rouzioux C, Capeau J, Müller-Trutwin M, Dereuddre-Bosquet N, Le Grand R, Lambotte O, Bourgeois C - PLoS Pathog. (2015)

Bottom Line: We detected cell-associated SIV DNA and RNA in the SVF and in sorted CD4+ T cells and macrophages from adipose tissue.Importantly, the production of HIV RNA was detected by in situ hybridization, and after the in vitro reactivation of sorted CD4+ T cells from adipose tissue.These observations open up new therapeutic strategies for limiting the size of the viral reservoir and decreasing low-grade chronic inflammation via the modulation of adipose tissue-related pathways.

View Article: PubMed Central - PubMed

Affiliation: Université Paris Sud, UMR 1184, Le Kremlin-Bicêtre, France; CEA, DSV/iMETI, IDMIT, Fontenay-aux-Roses, France; INSERM, U1184, Immunology of Viral Infections and Autoimmune Diseases, Le Kremlin-Bicêtre, France.

ABSTRACT
Two of the crucial aspects of human immunodeficiency virus (HIV) infection are (i) viral persistence in reservoirs (precluding viral eradication) and (ii) chronic inflammation (directly associated with all-cause morbidities in antiretroviral therapy (ART)-controlled HIV-infected patients). The objective of the present study was to assess the potential involvement of adipose tissue in these two aspects. Adipose tissue is composed of adipocytes and the stromal vascular fraction (SVF); the latter comprises immune cells such as CD4+ T cells and macrophages (both of which are important target cells for HIV). The inflammatory potential of adipose tissue has been extensively described in the context of obesity. During HIV infection, the inflammatory profile of adipose tissue has been revealed by the occurrence of lipodystrophies (primarily related to ART). Data on the impact of HIV on the SVF (especially in individuals not receiving ART) are scarce. We first analyzed the impact of simian immunodeficiency virus (SIV) infection on abdominal subcutaneous and visceral adipose tissues in SIVmac251 infected macaques and found that both adipocytes and adipose tissue immune cells were affected. The adipocyte density was elevated, and adipose tissue immune cells presented enhanced immune activation and/or inflammatory profiles. We detected cell-associated SIV DNA and RNA in the SVF and in sorted CD4+ T cells and macrophages from adipose tissue. We demonstrated that SVF cells (including CD4+ T cells) are infected in ART-controlled HIV-infected patients. Importantly, the production of HIV RNA was detected by in situ hybridization, and after the in vitro reactivation of sorted CD4+ T cells from adipose tissue. We thus identified adipose tissue as a crucial cofactor in both viral persistence and chronic immune activation/inflammation during HIV infection. These observations open up new therapeutic strategies for limiting the size of the viral reservoir and decreasing low-grade chronic inflammation via the modulation of adipose tissue-related pathways.

No MeSH data available.


Related in: MedlinePlus

The influence of SIV infection on T cell differentiation and activation status.(A) The naïve and memory CD4+ T cell subset distribution in SCAT and VAT from SIV-infected or non-infected animals. Representative dot plots showing the gating strategies used to define Tn, Tcm, Ttm and Tem subsets among the CD4+ T cells, based on CD28, CD95 (upper dot plot, SCAT and VAT samples). CCR5 expression and the FMO profile in CD28+CD95+ fractions are shown (lower dot plot: VAT sample). The right-hand panels show the distribution of CD4+ T cells among the various subsets in non-infected animals (n = 5, open column) and SIV-infected animals (n = 7, filled column). (B) CD69 expression on CD4+ T cells recovered from SCAT, VAT and PBMCs from SIV-infected or non-infected animals. Representative dot plots for SCAT and VAT (left panel) and the percentages of CD69-expressing CD4+ T cells in SCAT, VAT and PBMCs from non-infected animals (n = 6, open columns) and SIV-infected animals (n = 7, filled columns) are shown. (C) HLA-DR expression on SCAT, VAT and PBMCs from SIV-infected or non-infected animals. Representative histograms showing HLA-DR expression on adipose-resident CD4+ and CD8+ T cells recovered from SCAT from non-infected (left panel) and SIV-infected animals (right-hand panel). HLA-DR expression histograms are shown in plain histogram. FMO staining (open histograms) was used to define the gating strategy. The percentage of HLA-DR-expressing cells among CD4+ and CD8+ T cells recovered from SCAT, VAT and PBMCs from non-infected animals (n = 6, open circles) and SIV-infected animals (n = 4–8, filled squares). Data are quoted as the median [interquartile range]. Significant differences in a Mann-Whitney non-parametric test are shown as * p<0.05; ** p<0.01.
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ppat.1005153.g004: The influence of SIV infection on T cell differentiation and activation status.(A) The naïve and memory CD4+ T cell subset distribution in SCAT and VAT from SIV-infected or non-infected animals. Representative dot plots showing the gating strategies used to define Tn, Tcm, Ttm and Tem subsets among the CD4+ T cells, based on CD28, CD95 (upper dot plot, SCAT and VAT samples). CCR5 expression and the FMO profile in CD28+CD95+ fractions are shown (lower dot plot: VAT sample). The right-hand panels show the distribution of CD4+ T cells among the various subsets in non-infected animals (n = 5, open column) and SIV-infected animals (n = 7, filled column). (B) CD69 expression on CD4+ T cells recovered from SCAT, VAT and PBMCs from SIV-infected or non-infected animals. Representative dot plots for SCAT and VAT (left panel) and the percentages of CD69-expressing CD4+ T cells in SCAT, VAT and PBMCs from non-infected animals (n = 6, open columns) and SIV-infected animals (n = 7, filled columns) are shown. (C) HLA-DR expression on SCAT, VAT and PBMCs from SIV-infected or non-infected animals. Representative histograms showing HLA-DR expression on adipose-resident CD4+ and CD8+ T cells recovered from SCAT from non-infected (left panel) and SIV-infected animals (right-hand panel). HLA-DR expression histograms are shown in plain histogram. FMO staining (open histograms) was used to define the gating strategy. The percentage of HLA-DR-expressing cells among CD4+ and CD8+ T cells recovered from SCAT, VAT and PBMCs from non-infected animals (n = 6, open circles) and SIV-infected animals (n = 4–8, filled squares). Data are quoted as the median [interquartile range]. Significant differences in a Mann-Whitney non-parametric test are shown as * p<0.05; ** p<0.01.

Mentions: We next evaluated the differentiation of adipose CD4+ and CD8+ T cells obtained from infected and non-infected animals (Figs 4 and S1). Testing for CD95, CD28 and CCR5 expression enabled us to identify naïve (Tn), central memory (Tcm), transitional memory (Ttm) and effector memory (Tem) subsets (Figs 4A and S1A) [55,56]. In both infected and non-infected animals, naïve CD4+ T cells (CD95- CD28int) were virtually absent, whereas the Tcm (CD95+ CD28+ CCR5-) fraction was predominant in both SCAT and VAT. Interestingly, this profile was specific to CD4+ T cells since CD8+ T cells from adipose tissue were essentially Tem (CD95+ CD28-) (S1 Fig). Among CD4+ T cells, the CD95+ CD28+ CD4+ T cell fraction which includes the two potential cellular CD4+ T cell reservoir, i.e. Tcm (CCR5-) and Ttm (CCR5+), accounted for 82.3% [69.0–89.0] of the total in SCAT and 77.6% [69.9–77.6] in VAT, vs. 45.3% [28.8–62.0] in peripheral blood mononuclear cells (PBMCs) (p = 0.001 and 0.014 respectively) (S2A and S2B Fig). Interestingly, we did not detect significant differences in any of the CD4+ T cell fractions when comparing adipose tissue from SIV-infected animals (n = 7) and non-infected animals (n = 5). To evaluate the proportion of resident memory T cells [57,58], we next determined CD69 expression on CD4+ T cells recovered from adipose tissue and (as a control) in PBMCs (Fig 4B). The fraction of CD4+ T cells expressing CD69 was significantly higher in adipose tissue than in PBMCs (p = 0.0003 for SCAT and 0.0034 for VAT). However, SIV infection was not associated with a significant difference in the proportion of CD69-expressing cells. Thus, the maintenance of normal CD4+ T cell numbers was associated with preservation of memory CD4+ T cell subset distribution in general as well as the resident CD4+ T cell memory distribution.


Adipose Tissue Is a Neglected Viral Reservoir and an Inflammatory Site during Chronic HIV and SIV Infection.

Damouche A, Lazure T, Avettand-Fènoël V, Huot N, Dejucq-Rainsford N, Satie AP, Mélard A, David L, Gommet C, Ghosn J, Noel N, Pourcher G, Martinez V, Benoist S, Béréziat V, Cosma A, Favier B, Vaslin B, Rouzioux C, Capeau J, Müller-Trutwin M, Dereuddre-Bosquet N, Le Grand R, Lambotte O, Bourgeois C - PLoS Pathog. (2015)

The influence of SIV infection on T cell differentiation and activation status.(A) The naïve and memory CD4+ T cell subset distribution in SCAT and VAT from SIV-infected or non-infected animals. Representative dot plots showing the gating strategies used to define Tn, Tcm, Ttm and Tem subsets among the CD4+ T cells, based on CD28, CD95 (upper dot plot, SCAT and VAT samples). CCR5 expression and the FMO profile in CD28+CD95+ fractions are shown (lower dot plot: VAT sample). The right-hand panels show the distribution of CD4+ T cells among the various subsets in non-infected animals (n = 5, open column) and SIV-infected animals (n = 7, filled column). (B) CD69 expression on CD4+ T cells recovered from SCAT, VAT and PBMCs from SIV-infected or non-infected animals. Representative dot plots for SCAT and VAT (left panel) and the percentages of CD69-expressing CD4+ T cells in SCAT, VAT and PBMCs from non-infected animals (n = 6, open columns) and SIV-infected animals (n = 7, filled columns) are shown. (C) HLA-DR expression on SCAT, VAT and PBMCs from SIV-infected or non-infected animals. Representative histograms showing HLA-DR expression on adipose-resident CD4+ and CD8+ T cells recovered from SCAT from non-infected (left panel) and SIV-infected animals (right-hand panel). HLA-DR expression histograms are shown in plain histogram. FMO staining (open histograms) was used to define the gating strategy. The percentage of HLA-DR-expressing cells among CD4+ and CD8+ T cells recovered from SCAT, VAT and PBMCs from non-infected animals (n = 6, open circles) and SIV-infected animals (n = 4–8, filled squares). Data are quoted as the median [interquartile range]. Significant differences in a Mann-Whitney non-parametric test are shown as * p<0.05; ** p<0.01.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4581628&req=5

ppat.1005153.g004: The influence of SIV infection on T cell differentiation and activation status.(A) The naïve and memory CD4+ T cell subset distribution in SCAT and VAT from SIV-infected or non-infected animals. Representative dot plots showing the gating strategies used to define Tn, Tcm, Ttm and Tem subsets among the CD4+ T cells, based on CD28, CD95 (upper dot plot, SCAT and VAT samples). CCR5 expression and the FMO profile in CD28+CD95+ fractions are shown (lower dot plot: VAT sample). The right-hand panels show the distribution of CD4+ T cells among the various subsets in non-infected animals (n = 5, open column) and SIV-infected animals (n = 7, filled column). (B) CD69 expression on CD4+ T cells recovered from SCAT, VAT and PBMCs from SIV-infected or non-infected animals. Representative dot plots for SCAT and VAT (left panel) and the percentages of CD69-expressing CD4+ T cells in SCAT, VAT and PBMCs from non-infected animals (n = 6, open columns) and SIV-infected animals (n = 7, filled columns) are shown. (C) HLA-DR expression on SCAT, VAT and PBMCs from SIV-infected or non-infected animals. Representative histograms showing HLA-DR expression on adipose-resident CD4+ and CD8+ T cells recovered from SCAT from non-infected (left panel) and SIV-infected animals (right-hand panel). HLA-DR expression histograms are shown in plain histogram. FMO staining (open histograms) was used to define the gating strategy. The percentage of HLA-DR-expressing cells among CD4+ and CD8+ T cells recovered from SCAT, VAT and PBMCs from non-infected animals (n = 6, open circles) and SIV-infected animals (n = 4–8, filled squares). Data are quoted as the median [interquartile range]. Significant differences in a Mann-Whitney non-parametric test are shown as * p<0.05; ** p<0.01.
Mentions: We next evaluated the differentiation of adipose CD4+ and CD8+ T cells obtained from infected and non-infected animals (Figs 4 and S1). Testing for CD95, CD28 and CCR5 expression enabled us to identify naïve (Tn), central memory (Tcm), transitional memory (Ttm) and effector memory (Tem) subsets (Figs 4A and S1A) [55,56]. In both infected and non-infected animals, naïve CD4+ T cells (CD95- CD28int) were virtually absent, whereas the Tcm (CD95+ CD28+ CCR5-) fraction was predominant in both SCAT and VAT. Interestingly, this profile was specific to CD4+ T cells since CD8+ T cells from adipose tissue were essentially Tem (CD95+ CD28-) (S1 Fig). Among CD4+ T cells, the CD95+ CD28+ CD4+ T cell fraction which includes the two potential cellular CD4+ T cell reservoir, i.e. Tcm (CCR5-) and Ttm (CCR5+), accounted for 82.3% [69.0–89.0] of the total in SCAT and 77.6% [69.9–77.6] in VAT, vs. 45.3% [28.8–62.0] in peripheral blood mononuclear cells (PBMCs) (p = 0.001 and 0.014 respectively) (S2A and S2B Fig). Interestingly, we did not detect significant differences in any of the CD4+ T cell fractions when comparing adipose tissue from SIV-infected animals (n = 7) and non-infected animals (n = 5). To evaluate the proportion of resident memory T cells [57,58], we next determined CD69 expression on CD4+ T cells recovered from adipose tissue and (as a control) in PBMCs (Fig 4B). The fraction of CD4+ T cells expressing CD69 was significantly higher in adipose tissue than in PBMCs (p = 0.0003 for SCAT and 0.0034 for VAT). However, SIV infection was not associated with a significant difference in the proportion of CD69-expressing cells. Thus, the maintenance of normal CD4+ T cell numbers was associated with preservation of memory CD4+ T cell subset distribution in general as well as the resident CD4+ T cell memory distribution.

Bottom Line: We detected cell-associated SIV DNA and RNA in the SVF and in sorted CD4+ T cells and macrophages from adipose tissue.Importantly, the production of HIV RNA was detected by in situ hybridization, and after the in vitro reactivation of sorted CD4+ T cells from adipose tissue.These observations open up new therapeutic strategies for limiting the size of the viral reservoir and decreasing low-grade chronic inflammation via the modulation of adipose tissue-related pathways.

View Article: PubMed Central - PubMed

Affiliation: Université Paris Sud, UMR 1184, Le Kremlin-Bicêtre, France; CEA, DSV/iMETI, IDMIT, Fontenay-aux-Roses, France; INSERM, U1184, Immunology of Viral Infections and Autoimmune Diseases, Le Kremlin-Bicêtre, France.

ABSTRACT
Two of the crucial aspects of human immunodeficiency virus (HIV) infection are (i) viral persistence in reservoirs (precluding viral eradication) and (ii) chronic inflammation (directly associated with all-cause morbidities in antiretroviral therapy (ART)-controlled HIV-infected patients). The objective of the present study was to assess the potential involvement of adipose tissue in these two aspects. Adipose tissue is composed of adipocytes and the stromal vascular fraction (SVF); the latter comprises immune cells such as CD4+ T cells and macrophages (both of which are important target cells for HIV). The inflammatory potential of adipose tissue has been extensively described in the context of obesity. During HIV infection, the inflammatory profile of adipose tissue has been revealed by the occurrence of lipodystrophies (primarily related to ART). Data on the impact of HIV on the SVF (especially in individuals not receiving ART) are scarce. We first analyzed the impact of simian immunodeficiency virus (SIV) infection on abdominal subcutaneous and visceral adipose tissues in SIVmac251 infected macaques and found that both adipocytes and adipose tissue immune cells were affected. The adipocyte density was elevated, and adipose tissue immune cells presented enhanced immune activation and/or inflammatory profiles. We detected cell-associated SIV DNA and RNA in the SVF and in sorted CD4+ T cells and macrophages from adipose tissue. We demonstrated that SVF cells (including CD4+ T cells) are infected in ART-controlled HIV-infected patients. Importantly, the production of HIV RNA was detected by in situ hybridization, and after the in vitro reactivation of sorted CD4+ T cells from adipose tissue. We thus identified adipose tissue as a crucial cofactor in both viral persistence and chronic immune activation/inflammation during HIV infection. These observations open up new therapeutic strategies for limiting the size of the viral reservoir and decreasing low-grade chronic inflammation via the modulation of adipose tissue-related pathways.

No MeSH data available.


Related in: MedlinePlus