In vivo administration of a JAK3 inhibitor during acute SIV infection leads to significant increases in viral load during chronic infection.
In vivo administration of a JAK3 inhibitor during acute SIV infection leads to significant increases in viral load during chronic infection.
复制标题
在急性SIV感染期间，体内给药JAK3抑制剂会导致慢性感染期间病毒载量显着增加。
DOI：
10.1371/journal.ppat.1003929
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发表时间：
2014-03
期刊：
影响因子：
6.7
通讯作者：
Ansari AA
中科院分区：
文献类型：
--
作者：
Takahashi Y;Byrareddy SN;Albrecht C;Brameier M;Walter L;Mayne AE;Dunbar P;Russo R;Little DM;Villinger T;Khowawisetsut L;Pattanapanyasat K;Villinger F;Ansari AA
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. In efforts to define the potential role of innate immune effector mechanisms in influencing the course of SIV infection during the acute infection period, our lab utilized the in vivo daily administration of 20 mg/kg orally of a compound called Tofacitinib (a Janus kinase 3 inhibitor) to a group of 15 rhesus macaques starting at day −6 and until day 28 post intravenous SIVmac239 infection. An additional group of 16 similarly SIV infected rhesus macaques served as a placebo control. This drug targets the JAK/STAT pathway that is utilized by cells including the NK cell lineage, a major cell of the innate immune system. The dosage utilized was based on extensive previous PK studies that resulted in a marked depletion of the NK cells. Of interest while such drug administration had no effect on plasma viral loads during acute infection, such drug administration led to significant increases in plasma and gastro-intestinal tissues (GIT) viral loads during chronic infection. A series of phenotypic/functional studies were performed to determine the mechanisms for this delayed effect and the correlates identified. These data are the first to document the effect of JAK-3 inhibitor during acute SIV infection with implications for HIV vaccine design.
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影响因子：
8.7
作者：
Cooper MA;Yokoyama WM
通讯作者：
Yokoyama WM
DOI：
10.1007/978-1-4419-5632-3_12
发表时间：
2011-01-01
期刊：
CROSSROADS BETWEEN INNATE AND ADAPTIVE IMMUNITY III
影响因子：
--
作者：
Ansari, Aftab A.;Mayne, Ann E.;Pattanapanyasat, Kovit
通讯作者：
Pattanapanyasat, Kovit
影响因子：
4.4
作者：
Deniz, Gunnur;Erten, Gaye;Akdis, Mubeccel
通讯作者：
Akdis, Mubeccel
统一依赖MHC的天然杀手细胞教育的概念。
影响因子：
16.8
作者：
Elliott JM;Yokoyama WM
通讯作者：
Yokoyama WM
影响因子：
6.7
作者：
Alpert MD;Harvey JD;Lauer WA;Reeves RK;Piatak M Jr;Carville A;Mansfield KG;Lifson JD;Li W;Desrosiers RC;Johnson RP;Evans DT
通讯作者：
Evans DT