A selective defect of IFN-gamma- but not of IFN-alpha-induced JAK/STAT pathway in a subset of U937 clones prevents the antiretroviral effect of IFN-gamma against HIV-1
C. Bovolenta et al., A selective defect of IFN-gamma- but not of IFN-alpha-induced JAK/STAT pathway in a subset of U937 clones prevents the antiretroviral effect of IFN-gamma against HIV-1, J IMMUNOL, 162(1), 1999, pp. 323-330
IFN-gamma induces transcription of several IFN-stimulated genes (ISGs), Rec
ently, the IFN-gamma-dependent Janus kinase (JAK)/STAT pathway has been sho
wn to mediate the activation of some ISGs, by the sequential phosphorylatio
n of two JAK kinases (JAK1 and JAK2) and of STAT1, Given that the JAK/STAT
is the major, but not the only pathway linked to the IFN-gamma R, aim of ou
r work was to investigate the signal-transduction pathway(s) by which IFN-g
amma exerts its effects on acute replication of HIV in monocytic cells, To
this end, we utilized clones previously derived from the U937 promonocytic
cell line, differing for their efficient (plus clones) or inefficient (minu
s clones) abilities of supporting HIV replication. Unlike IFN-alpha, IFN-ga
mma did not inhibit HIV replication in plus clones, whereas virus productio
n in minus cells was efficiently inhibited by both types of IFN, Plus clone
s generated a JAK/STAT signal-transduction pathway in response to IFN-alpha
, but not IFN-gamma, In contrast, minus clones responded to either cytokine
s. The functional defect of plus clones in response to IFN-gamma was correl
ated to a selective defect of IFN-gamma R2, but not IFN-gamma R1, membrane
expression. Surprisingly enough, IFN-gamma stimulation of plus clones induc
ed IFN-stimulated gene factor 3 (ISGF3 gamma), These results strongly suppo
rt the hypothesis that the JAK/STAT pathway is responsible for the antiretr
oviral effect of IFN-gamma, and further provide evidence for a potential se
cond pathway triggered by IFN-gamma in the absence of IFN-gamma R2 chain ce
ll surface expression and involving ISGF3 gamma.