In vivo administration of a JAK3 inhibitor to chronically siv infected rhesus macaques leads to NK cell depletion associated with transient modest increase in viral loads.
Innate immune responses are reasoned to play an important role during both acute and chronic SIV infection and play a deterministic role during the acute stages on the rate of infection and disease progression. NK cells are an integral part of the innate immune system but their role in influencing the course of SIV infection has been a subject of debate. As a means to delineate the effect of NK cells on SIV infection, use was made of a Janus kinase 3 (JAK3) inhibitor that has previously been shown to be effective in the depletion of NK cells in vivo in nonhuman primates (NHP). Extensive safety and in vitro/in vivo PK studies were conducted and an optimal dose that depletes NK cells and NK cell function in vivo identified. Six chronically SIV infected rhesus macaques, 3 with undetectable/low plasma viral loads and 3 with high plasma viral loads were administered a daily oral dose of 10 mg/kg for 35 days. Data obtained showed that, at the dose tested, the major cell lineage affected both in the blood and the GI tissues were the NK cells. Such depletion appeared to be associated with a transient increase in plasma and GI tissue viral loads. Whereas the number of NK cells returned to baseline values in the blood, the GI tissues remained depleted of NK cells for a prolonged period of time. Recent findings show that the JAK3 inhibitor utilized in the studies reported herein has a broader activity than previously reported with dose dependent effects on both JAK2 and JAK1 suggests that it is likely that multiple pathways are affected with the administration of this drug that needs to be taken into account. The findings reported herein are the first studies on the use of a JAK3 inhibitor in lentivirus infected NHP.
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
Yoshiaki
Y
Takahashi
Ann E
AE
Mayne
Ladawan
L
Khowawisetsut
Kovit
K
Pattanapanyasat
Dawn
D
Little
Francois
F
Villinger
Aftab A
AA
Ansari
D000818:Animals; D002908:Chronic Disease; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors*; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology / Q000821:virology; D008253:Macaca mulatta / Q000276:immunology / Q000821:virology*; D008297:Male; D011494:Protein Kinases / Q000008:administration & dosage / Q000494:pharmacology*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000097:blood / Q000201:enzymology / Q000276:immunology*; D015302:Simian Immunodeficiency Virus / Q000276:immunology* / Q000502:physiology; D019562:Viral Load / Q000187:drug effects*
D011494:Protein Kinases; D053616:Janus Kinase 3