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Maraviroc induces HIV production in a RCT and in vitro,
potentially via the NF-kB pathway
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The Immunomodulatory Effects of Maraviroc Intensification among ART-suppressed Patients with Incomplete CD4 Recovery.......
http://www.natap.org/2011/CROI/croi_39.htm
Reported by Jules Levin
CROI 2015 Seattle, WA/2016 too
J Symons1, W de Spiegelaere2, AMJ Wensing1, J Drylewicz3, A Middel4, AIM Hoepelman4, K Tesselaar3, L Vandekerckhove2, SFL van Lelyveld4, M Nijhuis1
1Department of Medical Microbiology, Virology, University Medical Centre Utrecht (UMCU), The Netherlands 2Department of Internal Medicine,
Ghent University, Belgium, 3Department of Immunology and 4Department of Internal Medicine and Infectious Diseases, UMCU, The Netherlands
Program abstract
Background: Recent data indicated that addition of maraviroc (MVC) to combination antiretroviral therapy (cART) increases immune activation. We investigated MVC induced cell activation and HIV production both in vivo during a MVC intensification trial and in vitro in donor peripheral blood mononuclear cells (PBMCs).
Methods: Using ultra-sensitive droplet digital PCR detailed longitudinal virological and immunological analysis was performed in 15 immune non-responders participating in a 48-week, double-blind, placebo-controlled MVC intensification trial. We assessed changes in total HIV DNA, 2-LTR circles, HIV RNA expression and NF-κB regulated gene expression (TNF-a, IFN-y, IL-10 and IL-6) per million PBMCs. Plasma levels of CCR5 ligands and immune activation markers (IL-2R, IP-10, sICAM and TWEAK) were analyzed by Luminex. Healthy donor PBMCs were infected with X4-tropic virus (HXB2) in absence or presence of increasing MVC levels and CA-p24 production was measured in culture supernatant.
Results: Patient characteristics, immunological and virological baseline values did not differ between the MVC intensification and placebo group. During the first eight weeks of intensification, a significant difference in relative HIV RNA expression was detected (MVC increase 1.7 fold (n=10); placebo decrease 4.2 fold (n=5); p=0.03). After eight weeks we also measured a 2.3 fold increase in plasma CCR5 ligand MIP-1β in the MVC group. During this period, a significant difference in NF-kB regulated gene expression was observed; expression increased in the MVC group and decreased in the placebo group (IFN-y p=0.02; IL-6 p=0.03). No differences in total cellular HIV DNA, 2-LTR circles and plasma activation markers were observed. In vitro assays demonstrated a significant dose-dependent increase in HIV production when MVC was added to PBMCs (2.2 fold). This significant increase in virus production was observed in all experiments (n=9) and at all dosages used (ranging from 1pM–1uM).
Conclusions: MVC intensification of cART in immunological non-responders slightly increases CCR5-ligand expression, NF-κB regulated gene expression and HIV RNA expression. This is in line with our in vitro observation of MVC induced HIV production. Together, these data indicate that MVC induces HIV production, potentially via upregulation of the NF-kB pathway which warrants further investigation into the potential consequences of this observation for the use of MVC as a pre-exposure prophylaxis.
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