Limits...
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

Localization of T cells in the adipose tissue of SIV-infected animals.Immunochemical analyses were performed on 11 SCAT and 10 VAT of SIV-infected animals. (A) Representative tissue sections showing CD4+ T cells within fat and far from capillaries (upper) and TiA1+ cells in the vicinity of the capillaries (lower). Scale bar: 50 μm, magnification x640 for CD4, x500 for TiA1. (B) Percentages of CD4+ T cells (open diamonds) and CD8+ T cells (filled diamonds) far from capillaries, corresponding to adipose-resident lymphocyte subsets. Depending on the location, cells were counted after immunochemical staining on SCAT and VAT sections from SIV-infected animals. Data are quoted as the median [interquartile range]. Significant differences in a Mann-Whitney non-parametric test are shown as ** p<0.01.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4581628&req=5

ppat.1005153.g003: Localization of T cells in the adipose tissue of SIV-infected animals.Immunochemical analyses were performed on 11 SCAT and 10 VAT of SIV-infected animals. (A) Representative tissue sections showing CD4+ T cells within fat and far from capillaries (upper) and TiA1+ cells in the vicinity of the capillaries (lower). Scale bar: 50 μm, magnification x640 for CD4, x500 for TiA1. (B) Percentages of CD4+ T cells (open diamonds) and CD8+ T cells (filled diamonds) far from capillaries, corresponding to adipose-resident lymphocyte subsets. Depending on the location, cells were counted after immunochemical staining on SCAT and VAT sections from SIV-infected animals. Data are quoted as the median [interquartile range]. Significant differences in a Mann-Whitney non-parametric test are shown as ** p<0.01.

Mentions: However, SIV infection was associated with differences in CD4+ and CD8+ T cell relative percentages (Fig 2B and 2C). The proportion of CD4+ T cells was significantly lower in SIV-infected macaques (17.6% [8.9–25] in SCAT, and 20.4% [11.0–28.0] in VAT) than in non-infected animals (40.0% [26.4–49.0] in SCAT, and 39.8% [23.6–48.7] in VAT; p = 0.0043 for SCAT, p = 0.0317 for VAT). Conversely, CD8+ T cell percentages were significantly higher in infected animals. The low CD4+ T cell percentages may reflect the CD4+ T cell depletion associated with SIV infection, whereas elevated CD8+ T cell percentages may reflect either a passive increase (due to CD4+ T cell decay), an active increase due to antiviral CD8 recruitment (as described in lungs after SIV infection [53,54]), or viral-independent local recruitment (as described in inflammatory adiposity [27]). To evaluate the direct impact of SIV infection on T cell subsets, we analyzed the numbers of CD4+ and CD8+ T cells recovered from adipose tissue of infected and non-infected groups of animals. Surprisingly, the CD4+ T cell number was not lower in infected animals, and there was even a non-significant trend towards CD4+ T cell accumulation in VAT (Fig 2C). In contrast, CD8+ T cell numbers in VAT were significantly higher (0.48 106 [0.29–0.67] in SIV-infected animals than in non-infected animals (0.14 106 cells/g [0.11–0.24]; p = 0.0205). A similar trend was observed for SCAT. Thus, the change in the CD4/CD8 ratio was mainly driven by an increase in CD8+ T cell numbers—a phenomenon that is often associated with inflammatory adiposity [27]. Lastly, we used immunochemical techniques to formally confirm the presence of T lymphocytes in adipose tissue (Fig 3A). Given that the recruitment of peripheral blood cells into adipose tissue during local inflammation has been described, we evaluated the T cell distribution both in the vicinity of the capillaries and far from the capillaries in SIV-infected animals. The CD4+ T cells were mainly located far from the capillaries, whereas CD8+ T cells were essentially located in the capillary area (Fig 3B). These observations are in accordance with massive influx of CD8+ T cells previously described in the context of adipose inflammation [27]. In contrast, CD4+ T cell counts in adipose tissue were only slightly affected by SIV infection, and most CD4+ T cells recovered in the SVF had not recently migrated into the adipose tissue from peripheral blood.


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)

Localization of T cells in the adipose tissue of SIV-infected animals.Immunochemical analyses were performed on 11 SCAT and 10 VAT of SIV-infected animals. (A) Representative tissue sections showing CD4+ T cells within fat and far from capillaries (upper) and TiA1+ cells in the vicinity of the capillaries (lower). Scale bar: 50 μm, magnification x640 for CD4, x500 for TiA1. (B) Percentages of CD4+ T cells (open diamonds) and CD8+ T cells (filled diamonds) far from capillaries, corresponding to adipose-resident lymphocyte subsets. Depending on the location, cells were counted after immunochemical staining on SCAT and VAT sections from SIV-infected animals. Data are quoted as the median [interquartile range]. Significant differences in a Mann-Whitney non-parametric test are shown as ** p<0.01.
© Copyright Policy
Related In: Results  -  Collection

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

ppat.1005153.g003: Localization of T cells in the adipose tissue of SIV-infected animals.Immunochemical analyses were performed on 11 SCAT and 10 VAT of SIV-infected animals. (A) Representative tissue sections showing CD4+ T cells within fat and far from capillaries (upper) and TiA1+ cells in the vicinity of the capillaries (lower). Scale bar: 50 μm, magnification x640 for CD4, x500 for TiA1. (B) Percentages of CD4+ T cells (open diamonds) and CD8+ T cells (filled diamonds) far from capillaries, corresponding to adipose-resident lymphocyte subsets. Depending on the location, cells were counted after immunochemical staining on SCAT and VAT sections from SIV-infected animals. Data are quoted as the median [interquartile range]. Significant differences in a Mann-Whitney non-parametric test are shown as ** p<0.01.
Mentions: However, SIV infection was associated with differences in CD4+ and CD8+ T cell relative percentages (Fig 2B and 2C). The proportion of CD4+ T cells was significantly lower in SIV-infected macaques (17.6% [8.9–25] in SCAT, and 20.4% [11.0–28.0] in VAT) than in non-infected animals (40.0% [26.4–49.0] in SCAT, and 39.8% [23.6–48.7] in VAT; p = 0.0043 for SCAT, p = 0.0317 for VAT). Conversely, CD8+ T cell percentages were significantly higher in infected animals. The low CD4+ T cell percentages may reflect the CD4+ T cell depletion associated with SIV infection, whereas elevated CD8+ T cell percentages may reflect either a passive increase (due to CD4+ T cell decay), an active increase due to antiviral CD8 recruitment (as described in lungs after SIV infection [53,54]), or viral-independent local recruitment (as described in inflammatory adiposity [27]). To evaluate the direct impact of SIV infection on T cell subsets, we analyzed the numbers of CD4+ and CD8+ T cells recovered from adipose tissue of infected and non-infected groups of animals. Surprisingly, the CD4+ T cell number was not lower in infected animals, and there was even a non-significant trend towards CD4+ T cell accumulation in VAT (Fig 2C). In contrast, CD8+ T cell numbers in VAT were significantly higher (0.48 106 [0.29–0.67] in SIV-infected animals than in non-infected animals (0.14 106 cells/g [0.11–0.24]; p = 0.0205). A similar trend was observed for SCAT. Thus, the change in the CD4/CD8 ratio was mainly driven by an increase in CD8+ T cell numbers—a phenomenon that is often associated with inflammatory adiposity [27]. Lastly, we used immunochemical techniques to formally confirm the presence of T lymphocytes in adipose tissue (Fig 3A). Given that the recruitment of peripheral blood cells into adipose tissue during local inflammation has been described, we evaluated the T cell distribution both in the vicinity of the capillaries and far from the capillaries in SIV-infected animals. The CD4+ T cells were mainly located far from the capillaries, whereas CD8+ T cells were essentially located in the capillary area (Fig 3B). These observations are in accordance with massive influx of CD8+ T cells previously described in the context of adipose inflammation [27]. In contrast, CD4+ T cell counts in adipose tissue were only slightly affected by SIV infection, and most CD4+ T cells recovered in the SVF had not recently migrated into the adipose tissue from peripheral blood.

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