Molecular and Cellular Biology, May 1999, p. 3645-3653, Vol. 19, No. 5
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Department of Pathology, Harvard Medical School, and Center for Blood Research, Boston, Massachusetts 02115
Received 16 December 1998/Returned for modification 27 January 1999/Accepted 9 February 1999
Human immunodeficiency virus type 1 (HIV-1) gene expression is
regulated by interactions between both viral and host factors. These
interactions are also responsible for changes in the expression of many
host cell genes, including cytokines and other immune regulators, which
may account for the state of immunological dysregulation that
characterizes HIV-1 infection. We have investigated the role of a host
cell protein, the transcription factor NFAT1, in HIV-1 pathogenesis. We show that NFAT1 interacts with Tat and that this interaction, which involves the major transactivation domain of NFAT1
and the amino-terminal region of Tat, results in a reciprocal modulatory interplay between the proteins: whereas Tat enhances NFAT1-driven transcription in Jurkat T cells, NFAT1 represses Tat-mediated transactivation of the HIV-1 long terminal repeat (LTR). Moreover, NFAT1 binds to the
B sites on the viral
LTR and negatively regulates NF-
B-mediated activation of HIV-1
transcription, by competing with NF-
B1 for its binding sites on the
HIV-1 LTR. Tat-mediated enhancement of NFAT1 transactivation may
explain the upregulation of interleukin 2 and other cytokines that
occurs during HIV-1 infection. We discuss the potentially opposing
roles of NFAT1 and another family member, NFAT2, in regulating gene transcription of HIV-1 and endogenous cytokine genes.
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