Interleukin-21 combined with ART reduces inflammation and viral reservoir in SIV-infected macaques
Luca Micci, … , Jason M. Brenchley, Mirko Paiardini
Luca Micci, … , Jason M. Brenchley, Mirko Paiardini
Published November 9, 2015
Citation Information: J Clin Invest. 2015;125(12):4497-4513. https://doi.org/10.1172/JCI81400.
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Research Article AIDS/HIV

Interleukin-21 combined with ART reduces inflammation and viral reservoir in SIV-infected macaques

Abstract

Despite successful control of viremia, many HIV-infected individuals given antiretroviral therapy (ART) exhibit residual inflammation, which is associated with non–AIDS-related morbidity and mortality and may contribute to virus persistence during ART. Here, we investigated the effects of IL-21 administration on both inflammation and virus persistence in ART-treated, SIV-infected rhesus macaques (RMs). Compared with SIV-infected animals only given ART, SIV-infected RMs given both ART and IL-21 showed improved restoration of intestinal Th17 and Th22 cells and a more effective reduction of immune activation in blood and intestinal mucosa, with the latter maintained through 8 months after ART interruption. Additionally, IL-21, in combination with ART, was associated with reduced levels of SIV RNA in plasma and decreased CD4+ T cell levels harboring replication-competent virus during ART. At the latest experimental time points, which were up to 8 months after ART interruption, plasma viremia and cell-associated SIV DNA levels remained substantially lower than those before ART initiation in IL-21–treated animals but not in controls. Together, these data suggest that IL-21 supplementation of ART reduces residual inflammation and virus persistence in a relevant model of lentiviral disease and warrants further investigation as a potential intervention for HIV infection.

Authors

Luca Micci, Emily S. Ryan, Rémi Fromentin, Steven E. Bosinger, Justin L. Harper, Tianyu He, Sara Paganini, Kirk A. Easley, Ann Chahroudi, Clarisse Benne, Sanjeev Gumber, Colleen S. McGary, Kenneth A. Rogers, Claire Deleage, Carissa Lucero, Siddappa N. Byrareddy, Cristian Apetrei, Jacob D. Estes, Jeffrey D. Lifson, Michael Piatak Jr., Nicolas Chomont, Francois Villinger, Guido Silvestri, Jason M. Brenchley, Mirko Paiardini

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Figure 1

Longitudinal variations in viremia and CD4+ T cell levels in IL-21–treated and control SIV-infected RMs.

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Longitudinal variations in viremia and CD4+ T cell levels in IL-21–treat...
(A). Schematic of the study design. Sixteen RMs were infected i.v. with 300 TCID50 SIVmac239 (day 0), and starting on day 60 p.i., treated with combination ART (PMPA, FTC, raltegravir, and ritonavir-boosted darunavir) for 7 months. Seven animals (ROc10 died on day 140 p.i. due to post-surgical [LN biopsy] complications) received 2 courses of IL-21 treatment (100 μg/kg s.c.) weekly for 6 weeks at the beginning (from days 67–105 p.i.) and at the end (from days 203–241 p.i.) of ART, as well as 4 additional administrations upon ART interruption (day 271 p.i.). The remaining 8 animals served as ART-treated controls. On day 270 p.i., ART was interrupted, and all the animals were monitored for 8 additional months. PB, RB, and LN biopsies were collected at the indicated time points. (B and C) Plasma SIVmac239 RNA levels expressed as copies/ml (LOD, 60 copies/ml, dashed line) are shown for each individual animal (B) and as an average (C) in IL-21–treated (orange circles) versus control (black squares) RMs. (D–G) CD4+ T cell levels, expressed as a fraction of live CD3+ T cells, were compared between IL-21–treated and control RMs in PB (D), RB (F), and LN (G). In PB, CD4+ T cells were also expressed as absolute counts (cells/μl blood; E). Gray shaded area represents the time of ART treatment, and the orange arrows mark IL-21 administrations. Averaged data are presented as the mean ± SEM. cART, combination ART.