The regulatory human immunodeficiency virus-1 (HIV-1) Tat protein shows ple
iotropic effects on the survival and growth of both HIV-1-infected and unin
fected CD4(+) T lymphocytes, In this study, we have demonstrated that low c
oncentrations (10 ng/ml) of extracellular Tat protein induce the expression
of both c-fos mRNA and protein in serum-starved Jurkat CD4(+) lymphoblasto
id T cells. Using deletion mutants, we demonstrates that the SRE, CRE and,
to a lesser extent, also the SIE domains tall placed in the first 356 bp of
c-fos promoter) play a key role in mediating the response to extracellular
Tat. Moreover, the ability of Tat to activate the transcriptional activity
of c-fos promoter was consistently decreased by pretreatment with the ERK/
MAPK kinase inhibitor PD98058. Activation of c-fos is functional as demonst
rated by induction of the AP-1 transcription factor, which is involved in t
he regulation of critical genes for the activation of T lymphocytes, such a
s interleukin 2. The Tat-mediated induction of c-fos and AP-1 in uninfected
lymphoid T cells mag contribute to explain the immune hyperactivation that
characterizes the progression to autoimmune deficiency syndrome and consti
tutes the optimal environment for HIV-1 replication, occurring predominantl
y in activated/proliferating CD4(+) T cells.