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.
Highlights
The general consensus opinion is that events during the acute infection period following pathogenic lentiviral infection of humans and nonhuman primates dictate the levels of peak viremia and the rate of disease progression [1,2,3]
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 to a group of 15 rhesus macaques starting at day 26 and until day 28 post intravenous SIVmac239 infection
This drug targets the JAK/STAT pathway that is utilized by cells including the natural killer (NK) cell lineage, a major cell of the innate immune system
Summary
The general consensus opinion is that events during the acute infection period following pathogenic lentiviral infection of humans and nonhuman primates dictate the levels of peak viremia and the rate of disease progression [1,2,3]. It is fair to state that our previously held view that this cell lineage only performs killing function and has no immunological memory has been over simplistic This cell lineage is known to require self-MHC education, become licensed, possess immunological memory, manifest regulatory function (NKregs) and even contribute to tissue regeneration [21,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43]
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