H. Tian et al., HIV ENVELOPE-DIRECTED SIGNALING ABERRANCIES AND CELL-DEATH OF CD4(-CELLS IN THE ABSENCE OF TCR CO-STIMULATION() T), International immunology, 8(1), 1996, pp. 65-74
HIV-1 infection in CD4(+) T cells initiates a viral cytopathic effect
(CPE) that is dependent on the activation of intracellular protein tyr
osine kinases (PTK). PTK in T cells are also activated during the cour
se of TCR or CD4 receptor engagement and the manner of receptor engage
ment may generate signals leading either to cell proliferation, tolera
nce induction (anergy) or programmed cell death (PCD), We have identif
ied PTK triggered during the interaction of cells stably expressing su
rface HIV envelope (gp120/gp41; HIVenv) and CD4(+) T cells, which lead
s to extensive and rapid individual cell death, We have found that thi
s killing is accompanied by tyrosine phosphorylation and activation of
the CD4-associated p56(ick) kinase, and by activation of a second mem
ber of the src family of PTK, p59(fyn) kinase, normally associated wit
h T cell stimulation through the TCR, Interestingly, in contrast with
normal T cell signaling, the zeta subunit of the TCR fails to become t
yrosine-phosphorylated during signaling accompanying HIV-directed cell
killing, Downstream activation of the ZAP-70 PTK also does not occur,
Unlike T cell apoptosis triggered by soluble HIVenv glycoproteins, wh
ich requires co-stimulation of CD4 and the antigen-specific TCR, T cel
l killing by membrane-associated HIVenv does not require TCR co-stimul
ation, because aberrant signaling and cell death are triggered by CD4(
+) but TCR(-) cell lines, These results are the first report where dua
l activation of the Lck and Fyn PTK does not result in normal downstre
am signaling through the ZAP PTK, We suggest by analogy to SCID result
ing from ZAP-70 mutations, that the dissociation of upstream PTK activ
ation from ZAP-70 signaling contributes to T cell depletion by HIV and
to the development of AIDS.