TY - JOUR
T1 - Role of IL-15 signaling in the pathogenesis of simian immunodeficiency virus infection in rhesus macaques
AU - Okoye, Afam A.
AU - DeGottardi, Maren Q.
AU - Fukazawa, Yoshinori
AU - Vaidya, Mukta
AU - Abana, Chike O.
AU - Konfe, Audrie L.
AU - Fachko, Devin N.
AU - Duell, Derick M.
AU - Li, He
AU - Lum, Richard
AU - Gao, Lina
AU - Park, Byung S.
AU - Skalsky, Rebecca L.
AU - Lewis, Anne D.
AU - Axthelm, Michael K.
AU - Lifson, Jeffrey D.
AU - Wong, Scott W.
AU - Picker, Louis J.
N1 - Publisher Copyright:
© 2019 by The American Association of Immunologists, Inc.
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
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U2 - 10.4049/jimmunol.1900792
DO - 10.4049/jimmunol.1900792
M3 - Article
C2 - 31653683
AN - SCOPUS:85075222501
SN - 0022-1767
VL - 203
SP - 2928
EP - 2943
JO - Journal of Immunology
JF - Journal of Immunology
IS - 11
ER -