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HIV+ Fat Tissue is a HIV Reservoir & Inflammation Occurs
Within the Fat Tissue due to HIV - 2 studies report
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2 studies report: (1) We hypothesized that adipose tissue could be a reservoir for HIV, and that adipocytes stimulate HIV production from CD4+ T cells........"Adipose tissue is a likely sanctuary site for HIV in ART-treated patients......[other] Major tissue reservoirs include lymphoid tissue (lymph nodes, spleen, thymus and bone marrow), gut-associated lymphoid tissue (GALT) and the central nervous system.......HIV provirus was detectable in AT-SVF from different fat depots (subcutaneous, abdominal visceral, deep neck) of all five patients studied, in association with decreased memory CD4+ and increased CD8+ T cells......IL6 expression is increased in adipose tissue in obesity and HIV-associated lipodystrophy.......(2) 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 thus identified adipose tissue as a crucial cofactor in both viral persistence and chronic immune activation/inflammation during HIV infection"
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The study with the link immediately below was published this week and the 2nd study was published in March 2015....
2 - HIV Reservoir in Fat Tissue: inflammation, lipodystrophies - (09/25/15)
New research shows that adipose tissue can act as a reservoir for HIV and increase inflammation in the body....."Long-term, this type of viral reservoir is a potential source of new infection"......"If you were to stop HIV medicines in the individual," said Hunt, "then the viruses in the fat are actually capable of restarting the infection."....In terms of finding a cure for HIV - in which the virus is eliminated completely - adipose tissue may come into play......."A bigger issue for somebody who is on treatment is that those cells are probably playing a role in the adipose tissue inflammation," said Koethe. "The consequences of that would be that those cells in the adipose tissue are likely contributing to metabolic disease in HIV."
While future studies may confirm adipose tissue as a source of inflammation in HIV patients, more research will be needed to develop a treatment that targets this tissue.........http://www.healthline.com/health-news/fat-tissue-may-be-source-of-inflammation-and-infection-in-hiv-patients-092415#3......The researchers "were able to pull out T cells from adipose tissue and detect HIV in them," said Koethe, who was not involved in either study. However, he added, the study "really gets much more into how the types of immune cells in adipose tissue are changing in HIV patients. And that's probably at the root of a lot of the diabetes and lipid problems that we're seeing."
"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."
"Overall, we were able to demonstrate the persistence of HIV DNA and RNA within stromal vascular cells in adipose tissue recovered from ART-treated HIV-infected patients.....Adipose inflammation may be a consequence of systemic inflammation, with in turn is worsened by adipose inflammation in a vicious circle.....this dataset strongly supports the hypothesis whereby adipose tissue constitutes an important viral reservoir. Adipose tissue may thus constitute a favorable environment for viral persistence for several reasons: (a) constant inflammation favors viral replication, (b) the presence of elevated fractions of activated and central memory CD4+ T cells, which are HIV's natural targets, (c) the potentially insufficient distribution of some antiretroviral drugs into adipose tissue [44], which may favor viral persistence, and (d) the specific metabolic and immune activity of adipose tissue, which may affect the effectiveness of immune responses [74]......our results open up new therapeutic strategies for limiting the size of viral reservoirs, chronic inflammation and associated comorbidities (via the modulation of adipose tissue related pathways rather than strictly immune pathways)."
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Human adipose tissue as a reservoir for memory CD4+ T cells and HIV
AIDS March 27 2015
Couturier, Jacoba; Suliburk, James W.b; Brown, Jeremy M.c; Luke, David J.d; Agarwal, Neetid; Yu, Xiaoyinge; Nguyen, Chie; Iyer, Dinakard; Kozinetz, Claudia A.e; Overbeek, Paul A.f,g; Metzker, Michael L.f; Balasubramanyam, Ashokd,h; Lewis, Dorothy E.a
aDivision of Infectious Diseases, Department of Internal Medicine, University of Texas Health Science Center at HoustonbDepartment of Surgery, Baylor College of Medicine, Houston, TexascDepartment of Biological Sciences, Louisiana State University, Baton Rouge, LouisianadDiabetes Research Center, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Baylor College of MedicineeDepartment of PediatricsfDepartment of Molecular and Human GeneticsgDepartment of Molecular and Cellular Biology, Baylor College of MedicinehEndocrine Service, Ben Taub General Hospital, Houston, Texas, USA.
Abstract
Objective: The objective of this study is to determine whether adipose tissue functions as a reservoir for HIV-1.
Design: We examined memory CD4+ T cells and HIV DNA in adipose tissue-stromal vascular fraction (AT-SVF) of five patients [four antiretroviral therapy (ART)-treated and one untreated]. To determine whether adipocytes stimulate CD4+ T cells and regulate HIV production, primary human adipose cells were cocultured with HIV-infected CD4+ T cells.
Methods: AT-SVF T cells were studied by flow cytometry, and AT-SVF HIV DNA (Gag and Env) was examined by nested PCR and sequence analyses. CD4+ T-cell activation and HIV production were measured by flow cytometry and ELISA.
Results: AT-SVF CD3+ T cells were activated (>60% CD69+) memory CD4+ and CD8+ T cells in uninfected and HIV-infected persons, but the AT-SVF CD4+/CD8+ ratio was lower in HIV patients. HIV DNA (Gag and Env) was detected in AT-SVF of all five patients examined by nested PCR, comparably to other tissues [peripheral blood mononuclear cell (PBMC), lymph node or thymus]. In coculture experiments, adipocytes increased CD4+ T-cell activation and HIV production approximately two to three-fold in synergy with gamma-chain cytokines interleukin (IL)-2, IL7 or IL15. These effects were mitigated by neutralizing antibodies against IL6 and integrin-α1ß1. Adipocytes also enhanced T-cell viability.
Conclusion: Adipose tissues of ART-treated patients harbour activated memory CD4+ T cells and HIV DNA. Adipocytes promote CD4+ T-cell activation and HIV production in concert with intrinsic adipose factors. Adipose tissue may be an important reservoir for HIV.
Introduction
Eradication of HIV is challenging because the virus persists in cellular and anatomic reservoirs despite antiretroviral therapy (ART) [1]. Primary cellular reservoirs include memory CD4+ T cells and macrophages; despite their low frequency (~1 per million), latently infected CD4+ T cells are the primary source of viral rebound in patients whose ART is interrupted [2]. Physiological induction of latent HIV in CD4+ T cells occurs via activation of CD3+/T-cell receptor (TCR) cytokines [interleukin (IL)-2, IL7, IL15, IL6 and tumour necrosis factor-alpha (TNFα)], Toll-like receptor (TLR) ligands or free fatty acids [3].Major tissue reservoirs include lymphoid tissue (lymph nodes, spleen, thymus and bone marrow), gut-associated lymphoid tissue (GALT) and the central nervous system.
Adipose tissue is a major endocrine organ with diverse functions and cellular composition. It is present mainly under the skin (subcutaneous adipose tissue) and around thoracoabdominal organs (visceral adipose tissue). The immune system is intimately associated with adipose tissue; every lymph node is encapsulated by adipose tissue, and adipocytes are abundant within bone marrow and in ageing thymus gland [4-6]. Adipose tissue is composed of mature adipocytes and the stromal-vascular fraction (SVF) that includes preadipocytes, mesenchymal stem cells, fibroblasts, endothelial cells and immune cells. Every type of leukocyte is found in adipose tissue, and adipose-resident CD4+ T cells resemble those in other tissues in that they have an activated memory phenotype (CD45RO+CD69+) [7-9]. Stimuli for adipose CD4+ T cells include cytokines (IL2, IL7, IL15, IL6, IL8 or TNFα) or interactions with adipose macrophages, dendritic cells or adipocytes [10,11]. Chemokines and receptors such as RANTES (regulated on activation, normal T-cell expressed and secreted) or CXCR3 (chemokine (C-X-C motif) receptor 3) are important for T-cell migration into adipose tissue, although the antigenic stimuli (microbial or lipids) and general functions (proinflammatory vs. anti-inflammatory) are still unclear [12,13]. Adipocytes themselves are unable to support HIV infection [14], but adipose cells could influence the pathogenesis of infected CD4+ T cells within adipose depots. We hypothesized that adipose tissue could be a reservoir for HIV, and that adipocytes stimulate HIV production from CD4+ T cells.
Discussion
Adipose tissue is a likely sanctuary site for HIV in ART-treated patients. Adipose tissue contains activated memory CD4+ T cells, the major cellular reservoir for HIV [1]. Adipose memory CD4+ T-cell numbers declined relative to CD8+ T-cells in HIV patients. Adipocytes potentiated CD4+ T-cell activation and HIV replication in vitro in the presence of IL2, IL7 or IL15, cytokines known to be produced in adipose depots [25-27].
HIV provirus was detectable in AT-SVF from different fat depots (subcutaneous, abdominal visceral, deep neck) of all five patients studied, in association with decreased memory CD4+ and increased CD8+ T cells (Fig. 1). Inversion of the CD4+/CD8+ ratio is also observed in peripheral blood and GALT of HIV patients [28]. Memory T cells in adipose tissue of healthy donors and HIV patients expressed high levels of CD69+, indicating activation. CD69+-high expression typically distinguishes resting memory T cells in peripheral blood from T cells in tissues [7], suggesting that blood contamination of AT-SVF samples was unlikely. Precise determination of viral copy number was limited due to cell numbers, but each nested PCR replicate contained approximately 1 x 105 AT-SVF cell equivalents of DNA, of which 1-10% were memory CD4+ T cells. Assuming one HIV copy per positive PCR product in AT-SVF CD4+ T cells, there could be one copy per 1 x 104 CD4+ T cells in adipose tissue, comparable to HIV DNA levels in other reservoirs [2,29]. However, the precise cellular source of this AT-SVF HIV, and contribution of infected macrophages, is still to be determined.
Adipose cells enhanced CD4+ T-cell activation and HIV replication with gamma-chain cytokines and inflammatory factors (Fig. 2). IL2, IL7 and IL15 are expressed in lymphoid and nonlymphoid tissues, including adipose tissue, and regulate T-cell homeostatic stimulation, proliferation and HIV infection [25-27]. A systemic elevation of these cytokines is also observed during primary infection or following ART interruption [30]. Synergy between adipose tissue and these cytokines has important implications for HIV persistence in lymphoid tissues such as bone marrow, thymus and gut-associated lymphoid tissue, which are intimately associated with adipocytes [4-6]. IL6 expression is increased in adipose tissue in obesity and HIV-associated lipodystrophy [23,24], and expression of VLA-1 by memory CD4 T cells is increased during activation in inflamed tissues [31,32]. VLA-1 ligands include collagens and fibronectin, which enhance CD4+ T-cell activation and HIV production [33,34]. In addition, adipose tissue reorganization during HIV lipodystrophy is partly due to breakdown of extracellular matrix and increased expression of collagens and fibronectin leading to fibrosis [19,35].
Adipose tissue may be a widespread sanctuary for HIV, and ongoing studies are investigating the replication-competence and infectiousness of AT-SVF virus, and whether adipose tissue presents a barrier to ART drugs. A better understanding of adipose tissue as a potential HIV reservoir and its mechanisms of viral induction will be important for effective viral eradication strategies.
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