Human adipose tissue as a reservoir for memory CD4+ T cells and HIV

Abstract

Objective 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 5 patients (4 ART-treated and 1 untreated). To determine if adipocytes stimulate CD4 T cells and regulate HIV production, primary human adipose cells were co-cultured 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 5 patients examined by nested PCR, comparably to other tissues (PBMC, lymph node, or thymus). In co-culture experiments, adipocytes increased CD4 T cell activation and HIV production ∼2-3 fold in synergy with gamma-chain cytokines IL2, IL7, or IL15. These effects were mitigated by neutralizing antibodies against IL6 and integrin-α1β1. Adipocytes also enhanced T cell viability. Conclusions Adipose tissues of ART-treated patients harbor 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.

Adipocytes impair efficacy of antiretroviral therapy

“…The results presented here demonstrate that adipocytes have significant impact on ART distribution and activity within AT, which is newly believed to constitute a reservoir for latently infected HIV-/SIV-infected CD4 T cells (Couturier et al, 2015; Damouche et al, 2015; Couturier et al, 2016; Damouche et al, 2017; Hsu et al, 2017; Koethe et al, 2017; Couturier et al, 2018). In particular, these data suggest that adipocytes markedly diminish the antiretroviral effectiveness of NRTIs, particularly tenofovir, which constitutes an important “backbone” component of many antiretroviral regimens and is a first line agent for the treatment of HIV infection.…”

“…They observed that NNRTI concentrations were significantly higher in AT lysates compared to PI concentrations, whereas N(t)RTIs were undetectable. Others and we have recently demonstrated that latently-infected CD4 T cells accumulate in AT and establish replication-competent reservoirs during chronic HIV infection, indicating the need for better understanding of antiretroviral pharmacology in AT (Couturier et al, 2015; Damouche et al, 2015; Couturier et al, 2016; Damouche et al, 2017; Hsu et al, 2017; Koethe et al, 2017; Couturier et al, 2018). …”

Total HIV-1 DNA, a Marker of Viral Reservoir Dynamics with Clinical Implications

“…Recently, adipose tissue, and particularly memory CD4 T cells in this tissue, has been identified as a potentially important HIV reservoir, with the detection of total viral DNA in untreated macaques but also in patients on effective treatment (176,177). This reservoir is inducible by ex vivo activation.…”

Human cytomegalovirus infection of human adipose-derived stromal/stem cells restricts differentiation along the adipogenic lineage

“…Consequently, adipose tissue has been suggested to be a reservoir for specific infectious agents. [12][13][14][15] Human cytomegalovirus (HCMV), a member of the b-herpesvirus family, is one of the most common viruses infecting adults, with the seropositive rate ranging from 60-99% globally. 16 It typically presents as an asymptomatic infection in healthy individuals but can be life-threatening in immunocompromised individuals such as organ and bone marrow transplant patients or individuals positive for HIV/ AIDS.…”