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IL-21 Reduces Inflammation and Virus Persistence in ART-Treated SIV-Infected Macaques
Luca Micci1, Emily Ryan1, Colleen McGary1, Sara Paganini1, Guido Silvestri1, Mike Piatak2, Jeffrey Lifson2, Francois Villinger1, Jason M. Brenchley3, Mirko Paiardini1
1 Yerkes National Primate Research Center, Emory University, Atlanta, GA, United States. 2 Leidos Biomedical Research, Inc, Frederick, MD, United States. 3 National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, MD, United States.
Background: Residual inflammation persists and critically contributes to non-AIDS-related morbidity/mortality in ART-treated, HIV-infected subjects. Furthermore, inflammation may contribute to HIV persistence during ART. Interleukin (IL)-21 regulates the differentiation and maintenance of IL-17- and IL-22- producing CD4 T cells, which depletion critically contributes to chronic immune activation and disease progression in HIV and SIV infection. In this study, we investigated the effects of Interleukin (IL)-21 administration in chronic, ART-treated SIV-infected rhesus macaques (RMs) on mucosal integrity, residual inflammation, and virus persistence.
Methods: Sixteen RMs were infected with SIVmac239 i.v. and, starting at day 60 post-infection, treated for seven months with PMPA, FTC, Raltegravir, Darunavir and Ritonavir. Eight RMs received IL-21-Fc (100 mg/kg, s.c., weekly for six weeks) at the beginning and the end of ART, with the other eight serving as ART- treated controls. Blood, lymph nodes and rectum were longitudinally collected, and the effects of IL-21 on inflammation, T cell subset levels, and viral persistence assessed. The Mann-Whitney test was used for statistical analyses.
Results: ART was very effective, with fully suppressed plasma viremia (<60 SIV-RNA copies/ml) in all RMs. Compared to ART-controls, ART+IL-21 RMs showed improved restoration of intestinal Th17 and Th22 cells (P<0.01 for both subsets). Remarkably, IL-21-treated RMs showed a faster and more pronounced reduction in the levels of activated (HLA-DR+CD38+) and proliferating (Ki-67+) T cells in rectum and blood during ART (P<0.01), and maintained level of T cell activation significantly lower than controls up to eight months following ART-interruption (P<0.01). Between days 75 to 200 on-ART, IL-21-treatment elicited a higher number of RMs with undetectable (<3 copies/mL) SIV-vRNA in plasma (P<0.03). Furthermore, rectal cell associated SIV-DNA levels were significantly reduced between d75 and d200 on-ART in IL-21-treated RMs (P<0.01) but not in controls. Finally, only IL-21-treated animals maintained plasma viral loads significantly lower than those at pre-ART up to eight months post-ART interruption.
Conclusions: These data provide evidence of a link between mucosal immunity, inflammation, and HIV persistence. Furthermore, they suggest that IL-21 may provide important therapeutic benefits when used as an adjunctive immunomodulatory agent in ART-suppressed HIV-infected individuals.