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B Factors1
The Picower Institute for Medical Research, Manhasset, NY 11030
Elevated levels of circulating IL-8, a potent chemotactic factor
for granulocytes and T lymphocytes, are found in HIV-infected
individuals. The HIV-1 transactivator protein Tat increased IL-8
secretion in T cell lines following CD3- and CD28-mediated
costimulation. Full-length Tat (Tat101) enhanced IL-8 transcription
through up-regulated transcription factor binding to the
CD28-responsive element (CD28RE) in the IL-8 promoter. Expression of
the Tat splice variant Tat72 (72 amino acids) also enhanced IL-8
production following T cell stimulation via a different, most likely
post-transcriptional, mechanism. The CD28RE in the IL-8 promoter was
characterized as a low-affinity NF-
B binding site recognized by the
transcription factors p50 (NF-B1), p65 (RelA) and c-rel.
Transcription factor binding to "classical" NF-B sites in the
HIV-1, the human IL-2, and lymphotoxin promoters, recognized by p50 and
p65 following CD3+28-mediated costimulation, was unaffected by Tat101
as was binding to the AP-1 motif in the IL-8 promoter. These
experiments identify the CD28RE in the IL-8 promoter as a
c-rel recognition site and a Tat101-responsive element. The
effect of Tat101 on CD28REs in the IL-8 promoter and the subsequent
up-regulation of IL-8 secretion is likely to contribute to the immune
dysregulation observed during HIV-1 infection.
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