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Title: In Vivo Administration of a JAK3 Inhibitor during Acute SIV Infection Leads to Significant Increases in Viral Load during Chronic Infection
Authors: Yoshiaki Takahashi
Siddappa N. Byrareddy
Christina Albrecht
Markus Brameier
Lutz Walter
Ann E. Mayne
Paul Dunbar
Robert Russo
Dawn M. Little
Tara Villinger
Ladawan Khowawisetsut
Kovit Pattanapanyasat
Francois Villinger
Aftab A. Ansari
Emory University School of Medicine
Deutsches Primatenzentrum
Mahidol University
Emory University
Keywords: Biochemistry, Genetics and Molecular Biology;Immunology and Microbiology
Issue Date: 1-Jan-2014
Citation: PLoS Pathogens. Vol.10, No.3 (2014)
Abstract: 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. © 2014 Takahashi et al.
ISSN: 15537374
Appears in Collections:Scopus 2011-2015

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