Role of IL-15 signaling in the pathogenesis of simian immunodeficiency virus infection in rhesus macaques

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

Research output: Contribution to journalArticle

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 g-herpesviruses.

Original languageEnglish (US)
Pages (from-to)2928-2943
Number of pages16
JournalJournal of Immunology
Volume203
Issue number11
DOIs
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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  • Cite this

    Okoye, A. A., DeGottardi, M. Q., Fukazawa, Y., Vaidya, M., Abana, C. O., Konfe, A. L., Fachko, D. N., Duell, D. M., Li, H., Lum, R., Gao, L., Park, B. S., Skalsky, R. L., Lewis, A. D., Axthelm, M. K., Lifson, J. D., Wong, S. W., & Picker, L. J. (2019). Role of IL-15 signaling in the pathogenesis of simian immunodeficiency virus infection in rhesus macaques. Journal of Immunology, 203(11), 2928-2943. https://doi.org/10.4049/jimmunol.1900792