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.
Highlights
Human immunodeficiency virus (HIV) infection is characterized by massive CD4+ T cell depletion in the intestinal mucosa and sustained systemic immune activation and inflammation
In similar experiments in ARTcontrolled human immunodeficiency virus (HIV)-infected patients, HIV DNA was detected in the stromal vascular fraction of adipose tissue
Replication-competent HIV was detected in ex vivo- activated, sorted adipose tissue CD4+ T cells from six aviremic, antiretroviral therapy (ART)-treated patients
Summary
Human immunodeficiency virus (HIV) infection is characterized by massive CD4+ T cell depletion in the intestinal mucosa (progressively affecting blood and lymphoid CD4+ T cells) and sustained systemic immune activation and inflammation. The advent of antiretroviral therapy (ART) has drastically changed the outcomes of HIV infection by enabling a reduction in the viral load and the restoration (at least in part) of CD4+ T cell counts. It has been suggested that microbial translocation is a potent factor in the maintenance of chronic immune activation/ inflammation [9], along with viral persistence, CD4+ T cell lymphopenia, Th17 loss, a change in the regulatory T cell balance, disruption of the lymph node architecture, viral co-infection, accelerated ageing, the side effects of some antiretroviral drugs, and individual susceptibility [2,10,11]). HIV-infected patients on ART are not always able to reestablish gut mucosa integrity and/or normal CD4+ T cell counts, and chronic, low-levels immune activation appears to persist [12]. These data suggest that (i) immune activation and chronic inflammation are driven by multiple factors and (ii) targeting several inflammatory mechanisms may achieve better immune restoration
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