In Vivo Administration of a JAK3 Inhibitor during Acute SIV Infection Leads to Significant Increases in Viral Load during Chronic Infection

PLoS Pathogens

Ladawan Khowawisetsut¹  Tara Villinger²  Paul Dunbar²  Yoshiaki Takahashi²  Robert Russo²  Ann E. Mayne²  Francois Villinger²  Dawn M. Little²  Siddappa N. Byrareddy²  Aftab A. Ansari³  Kovit Pattanapanyasat⁴  Christina Albrecht⁵  Markus Brameier⁵  Lutz Walter⁵ 

[1] Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand;Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America;Division of Pathology, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, United States of America;Office for Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand;Primate Genetics Laboratory, German Primate Center, Leibniz-Institute for Primate Research, Göttingen, Germany

关键词: NK cells;    T cells;    SIV;    Viral load;    Monkeys;    Blood plasma;    Macaque;    Rhesus monkeys;   

DOI  :  10.1371/journal.ppat.1003929

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

The studies reported herein are the first to document the effect of the in vivo administration of a JAK3 inhibitor for defining the potential role of NK cells during acute SIV infection of a group of 15 rhesus macaques (RM). An additional group of 16 MHC/KIR typed RM was included as controls. The previously optimized in vivo dose regimen (20 mg/kg daily for 35 days) led to a marked depletion of each of the major NK cell subsets both in the blood and gastro-intestinal tissues (GIT) during acute infection. While such depletion had no detectable effects on plasma viral loads during acute infection, there was a significant sustained increase in plasma viral loads during chronic infection. While the potential mechanisms that lead to such increased plasma viral loads during chronic infection remain unclear, several correlates were documented. Thus, during acute infection, the administration of the JAK3 inhibitor besides depleting all NK cell subsets also decreased some CD8+ T cells and inhibited the mobilization of the plasmacytoid dendritic cells in the blood and their localization to the GIT. Of interest is the finding that the administration of the JAK3 inhibitor during acute infection also resulted in the sustained maintenance during chronic infection of a high number of naïve and central memory CD4+ T cells, increases in B cells in the blood, but decreases in the frequencies and function of NKG2a+ NK cells within the GIT and blood, respectively. These data identify a unique role for JAK3 inhibitor sensitive cells, that includes NK cells during acute infection that in concert lead to high viral loads in SIV infected RM during chronic infection without affecting detectable changes in antiviral humoral/cellular responses. Identifying the precise mechanisms by which JAK3 sensitive cells exert their influence is critical with important implications for vaccine design against lentiviruses.

【 授权许可】

CC BY