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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 adipocyte and SVF cell density.(A) Representative adipose tissue sections of SIV-infected and non-infected macaques. Scale bar: 50μm, magnification x 250. (B) The adipocyte density (numbers per HPF) in SCAT and VAT from 5 to 7 non-infected animals (SIV-) and 7 SIV-infected animals (SIV+). (C) Adipose tissue dissociation and counting of cells in the SVF was performed with 20 SIV+ animals and 10 SIV- animals. Counts are expressed per gram of adipose tissue. (D, E) Flow cytometry of the recovered SVF, yielding the proportion (D) and number (E) of CD45-expressing cells per gram of tissue. The analysis was performed for both SCAT and VAT; SIV- animals (n = 10) are represented by open circles and SIV+ animals (n = 12) are represented by 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.g001: The influence of SIV infection on adipocyte and SVF cell density.(A) Representative adipose tissue sections of SIV-infected and non-infected macaques. Scale bar: 50μm, magnification x 250. (B) The adipocyte density (numbers per HPF) in SCAT and VAT from 5 to 7 non-infected animals (SIV-) and 7 SIV-infected animals (SIV+). (C) Adipose tissue dissociation and counting of cells in the SVF was performed with 20 SIV+ animals and 10 SIV- animals. Counts are expressed per gram of adipose tissue. (D, E) Flow cytometry of the recovered SVF, yielding the proportion (D) and number (E) of CD45-expressing cells per gram of tissue. The analysis was performed for both SCAT and VAT; SIV- animals (n = 10) are represented by open circles and SIV+ animals (n = 12) are represented by 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 first determined the impact of SIV infection on adipocyte density (as evaluated by microscopy) (Fig 1A). Adipocyte density in both SCAT and VAT was markedly higher in SIV-infected macaques than in non-infected animals (median [interquartile range] number of adipocytes per field in SCAT: 51 [31–90] in infected animals and 17 [13–26] in controls, p = 0.032; in VAT: 64 [60–95] in infected animals and 31 [21–32] in controls, p = 0.0059) (Fig 1B). We also counted SVF cells harvested from SCAT and VAT in infected and non-infected animals (Fig 1C). To enable a valid comparison, SVF cell counts were expressed per gram of adipose tissue. In line with previous publications [47,52], we found that non-infected animals had significantly higher numbers of SVF cells in VAT than in SCAT (p = 0.009). Significantly higher SVF cell counts were detected in SCAT and VAT from infected animals than in non-infected animals (p<0.05 for both tissues).


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 adipocyte and SVF cell density.(A) Representative adipose tissue sections of SIV-infected and non-infected macaques. Scale bar: 50μm, magnification x 250. (B) The adipocyte density (numbers per HPF) in SCAT and VAT from 5 to 7 non-infected animals (SIV-) and 7 SIV-infected animals (SIV+). (C) Adipose tissue dissociation and counting of cells in the SVF was performed with 20 SIV+ animals and 10 SIV- animals. Counts are expressed per gram of adipose tissue. (D, E) Flow cytometry of the recovered SVF, yielding the proportion (D) and number (E) of CD45-expressing cells per gram of tissue. The analysis was performed for both SCAT and VAT; SIV- animals (n = 10) are represented by open circles and SIV+ animals (n = 12) are represented by 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.
© Copyright Policy
Related In: Results  -  Collection

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

ppat.1005153.g001: The influence of SIV infection on adipocyte and SVF cell density.(A) Representative adipose tissue sections of SIV-infected and non-infected macaques. Scale bar: 50μm, magnification x 250. (B) The adipocyte density (numbers per HPF) in SCAT and VAT from 5 to 7 non-infected animals (SIV-) and 7 SIV-infected animals (SIV+). (C) Adipose tissue dissociation and counting of cells in the SVF was performed with 20 SIV+ animals and 10 SIV- animals. Counts are expressed per gram of adipose tissue. (D, E) Flow cytometry of the recovered SVF, yielding the proportion (D) and number (E) of CD45-expressing cells per gram of tissue. The analysis was performed for both SCAT and VAT; SIV- animals (n = 10) are represented by open circles and SIV+ animals (n = 12) are represented by 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 first determined the impact of SIV infection on adipocyte density (as evaluated by microscopy) (Fig 1A). Adipocyte density in both SCAT and VAT was markedly higher in SIV-infected macaques than in non-infected animals (median [interquartile range] number of adipocytes per field in SCAT: 51 [31–90] in infected animals and 17 [13–26] in controls, p = 0.032; in VAT: 64 [60–95] in infected animals and 31 [21–32] in controls, p = 0.0059) (Fig 1B). We also counted SVF cells harvested from SCAT and VAT in infected and non-infected animals (Fig 1C). To enable a valid comparison, SVF cell counts were expressed per gram of adipose tissue. In line with previous publications [47,52], we found that non-infected animals had significantly higher numbers of SVF cells in VAT than in SCAT (p = 0.009). Significantly higher SVF cell counts were detected in SCAT and VAT from infected animals than in non-infected animals (p<0.05 for both tissues).

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