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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 adipose tissue macrophage numbers and phenotypes.(A) The percentage of CD14-expressing cells among CD45+ cells recovered in the SVF from SCAT and VAT from non-infected animals (open circles, n = 13) and SIV-infected animals (filled squares, n = 9). (B) Representative adipose tissue sections, confirming the presence of macrophages in adipose tissue in immunochemical preparations (CD68 staining). Scale bar: 50 μm, magnification x400. (C, D) Analyses of CD206 and CD163 expression on adipose-resident CD14-expressing cells recovered from SCAT (C) and PBMCs (D) from non-infected animals (open circles, n = 11) and SIV-infected animals (filled squares, n = 9). CD206-expressing fractions were not detected in PBMCs. Gating strategies are shown in S4 Fig. Data are quoted as the median [interquartile range]. Significant differences in a Mann-Whitney non-parametric test are shown as * p<0.05.
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ppat.1005153.g005: The influence of SIV infection on adipose tissue macrophage numbers and phenotypes.(A) The percentage of CD14-expressing cells among CD45+ cells recovered in the SVF from SCAT and VAT from non-infected animals (open circles, n = 13) and SIV-infected animals (filled squares, n = 9). (B) Representative adipose tissue sections, confirming the presence of macrophages in adipose tissue in immunochemical preparations (CD68 staining). Scale bar: 50 μm, magnification x400. (C, D) Analyses of CD206 and CD163 expression on adipose-resident CD14-expressing cells recovered from SCAT (C) and PBMCs (D) from non-infected animals (open circles, n = 11) and SIV-infected animals (filled squares, n = 9). CD206-expressing fractions were not detected in PBMCs. Gating strategies are shown in S4 Fig. Data are quoted as the median [interquartile range]. Significant differences in a Mann-Whitney non-parametric test are shown as * p<0.05.

Mentions: We next evaluated the changes among adipose macrophages (Fig 5), which are involved both in innate immunity and adipose homeostasis. At present, there is no clear phenotypic strategy for identifying tissue-resident macrophages and defining their activation profile. The pro-inflammatory (M1) versus anti-inflammatory (M2) distinction (commonly used in murine models) may not reflect the great heterogeneity of macrophage phenotypes in tissues. Indeed, macrophages probably develop across a continuum, with anti-inflammatory to pro-inflammatory profiles. In the present study, we considered macrophages to be CD45+CD3-CD14+ cells. The proportion of macrophages among CD45+ cells in SCAT was greater in SIV-infected animals than in non-infected animals (Fig 5A). A similar trend was observed in VAT. These findings are in line with the macrophage accumulation previously described in the context of adipose inflammation [26]. We confirmed the presence of macrophages in adipose tissue by performing immunohistochemical analyses (CD68 staining) of tissue sections (Fig 5B).


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 adipose tissue macrophage numbers and phenotypes.(A) The percentage of CD14-expressing cells among CD45+ cells recovered in the SVF from SCAT and VAT from non-infected animals (open circles, n = 13) and SIV-infected animals (filled squares, n = 9). (B) Representative adipose tissue sections, confirming the presence of macrophages in adipose tissue in immunochemical preparations (CD68 staining). Scale bar: 50 μm, magnification x400. (C, D) Analyses of CD206 and CD163 expression on adipose-resident CD14-expressing cells recovered from SCAT (C) and PBMCs (D) from non-infected animals (open circles, n = 11) and SIV-infected animals (filled squares, n = 9). CD206-expressing fractions were not detected in PBMCs. Gating strategies are shown in S4 Fig. Data are quoted as the median [interquartile range]. Significant differences in a Mann-Whitney non-parametric test are shown as * p<0.05.
© Copyright Policy
Related In: Results  -  Collection

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

ppat.1005153.g005: The influence of SIV infection on adipose tissue macrophage numbers and phenotypes.(A) The percentage of CD14-expressing cells among CD45+ cells recovered in the SVF from SCAT and VAT from non-infected animals (open circles, n = 13) and SIV-infected animals (filled squares, n = 9). (B) Representative adipose tissue sections, confirming the presence of macrophages in adipose tissue in immunochemical preparations (CD68 staining). Scale bar: 50 μm, magnification x400. (C, D) Analyses of CD206 and CD163 expression on adipose-resident CD14-expressing cells recovered from SCAT (C) and PBMCs (D) from non-infected animals (open circles, n = 11) and SIV-infected animals (filled squares, n = 9). CD206-expressing fractions were not detected in PBMCs. Gating strategies are shown in S4 Fig. Data are quoted as the median [interquartile range]. Significant differences in a Mann-Whitney non-parametric test are shown as * p<0.05.
Mentions: We next evaluated the changes among adipose macrophages (Fig 5), which are involved both in innate immunity and adipose homeostasis. At present, there is no clear phenotypic strategy for identifying tissue-resident macrophages and defining their activation profile. The pro-inflammatory (M1) versus anti-inflammatory (M2) distinction (commonly used in murine models) may not reflect the great heterogeneity of macrophage phenotypes in tissues. Indeed, macrophages probably develop across a continuum, with anti-inflammatory to pro-inflammatory profiles. In the present study, we considered macrophages to be CD45+CD3-CD14+ cells. The proportion of macrophages among CD45+ cells in SCAT was greater in SIV-infected animals than in non-infected animals (Fig 5A). A similar trend was observed in VAT. These findings are in line with the macrophage accumulation previously described in the context of adipose inflammation [26]. We confirmed the presence of macrophages in adipose tissue by performing immunohistochemical analyses (CD68 staining) of tissue sections (Fig 5B).

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