https://orcid.org/0000-0003-1646-8102
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Afam A Okoye, Maren Q DeGottardi, Yoshinori Fukazawa, Mukta Vaidya, Chike O Abana, Audrie L Konfe, Devin N Fachko, Derick M Duell, He Li, Richard Lum, Lina Gao, Byung S Park, Rebecca L Skalsky, Anne D Lewis, Michael K Axthelm, Jeffrey D Lifson, Scott W Wong, Louis J Picker, Role of IL-15 Signaling in the Pathogenesis of Simian Immunodeficiency Virus Infection in Rhesus Macaques, The Journal of Immunology, Volume 203, Issue 11, December 2019, Pages 2928–2943, https://doi.org/10.4049/jimmunol.1900792
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Abstract
Although IL-15 has been implicated in the pathogenic hyperimmune activation that drives progressive HIV and SIV infection, as well as in the generation of HIV/SIV target cells, it also supports NK and T cell homeostasis and effector activity, potentially benefiting the host. To understand the role of IL-15 in SIV infection and pathogenesis, we treated two cohorts of SIVmac239-infected rhesus macaques (RM; Macaca mulatta), one with chronic infection, the other with primary infection, with a rhesusized, IL-15–neutralizing mAb (versus an IgG isotype control) for up to 10 wk (n = 7–9 RM per group). In both cohorts, anti–IL-15 was highly efficient at blocking IL-15 signaling in vivo, causing 1) profound depletion of NK cells in blood and tissues throughout the treatment period; 2) substantial, albeit transient, depletion of CD8+ effector memory T cells (TEM) (but not the naive and central memory subsets); and 3) CD4+ and CD8+ TEM hyperproliferation. In primary infection, reduced frequencies of SIV-specific effector T cells in an extralymphoid tissue site were also observed. Despite these effects, the kinetics and extent of SIV replication, CD4+ T cell depletion, and the onset of AIDS were comparable between anti–IL-15– and control-treated groups in both cohorts. However, RM treated with anti–IL-15 during primary infection manifested accelerated reactivation of RM rhadinovirus. Thus, IL-15 support of NK cell and TEM homeostasis does not play a demonstrable, nonredundant role in SIV replication or CD4+ T cell deletion dynamics but may contribute to immune control of oncogenic γ-herpesviruses.
