Abstract
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.
Highlights
The fact that the net outcome of host-virus interactions during ‘‘acute’’ infection of both human HIV-1 infection and SIV infection of nonhuman primates dictates the rate of disease progression suggests that properties unique to the incoming virus and the quality and/or quantity of host ‘‘innate’’ immune effector mechanisms must play a deterministic role [1]
In the studies reported we studied the phosphorylation of STAT5, which is mediated by several Janus kinases (JAKs), including Janus kinase 3 (JAK3) to monitor the activity of the JAK3 inhibitor
Based on the results of phenotypic analyses and the natural killer (NK) cell functional studies it was decided that a loading dose of 20 mg/kg followed by a daily dose of 10 mg/kg in adult monkeys would provide appropriate trough levels to deplete NK cells and was the dose to utilize and this dose level was utilized for all subsequent studies
Summary
The fact that the net outcome of host-virus interactions during ‘‘acute’’ infection of both human HIV-1 infection and SIV infection of nonhuman primates dictates the rate of disease progression suggests that properties unique to the incoming virus and the quality and/or quantity of host ‘‘innate’’ immune effector mechanisms must play a deterministic role [1]. Studies utilizing single pools of stock SIV to infect groups of rhesus macaques showed a wide range of plasma and cellular viral loads at set point and diverse clinical outcome ranging from Elite Controllers to Fast Progressors [6,7,8,9] These latter results suggest that while properties unique to the virus are important, the host innate and early adaptive immune effector mechanisms must play a dominant role during this acute infection period. The precise cell lineages that play this important role and the mechanisms by which innate and/or early adaptive immune effector cells mediate this important effect remains elusive
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