Project Details


Progression of human immunodeficiency virus (HIV) infection
resulting in the development of AIDS, is associated with increased virus
replication. Replication of HIV, in turn, is dependent on a number of
cellular transcriptional factors that regulate viral RNA synthesis.
Factors that interact with the enhancer present in the HIV long terminal
repeat (LTR) are critical for activation of viral transcription. A
number of factors that bind to HIV enhancer sequences have been
identified, including an inducible binding activity called NF-kappaB
which is composed of multiple polypeptides, several of which are members
of the rel oncogene family. These include the p5O/NF-kappaB protein and
the human c-rel protein. Another member of this family, v-rel, has
recently been shown to inhibit NF-kappaB-mediated LTR activation. The
objectives of this project are -to: 1) characterize the interactions
between re/-family proteins and the HIV LTR; 2) examine the role that
re/-related proteins play in the regulation of HIV replication and
activation; and 3) identify novel NF-kappaB and re/-related proteins that
may participate in HIV regulation. The information that will be gained
from these studies will be used in the design and analysis of re/-related
inhibitors of HIV expression. Studies of the interactions between re/-family proteins and the HIV
LTR will involve mutagenesis of the v-rel, c-rel and NF-kappaB proteins
to map the domains responsible for DNAbinding, dimerization and
transcriptional activation of the HIV LTR. These mutants will be
analyzed for their ability to activate or inhibit LTR function. The
specific LTR sequences mediating rel transcriptional effects will be
defined using mutant HIV LTRs containing alterations in the NFkappaB and
Spl binding motifs. The role of re/-related proteins in the regulation of HIV
replication will be studied in both productive viral replication and
activation of latent proviruses in chronically-infected cells. The
contributions of various re/-related proteins to HIV. expression will be
analyzed in these systems, and the ability of mutant rel proteins to
block HIV production will be tested. Finally, a series of low stringency hybridization and cloning
experiments will be used to identify novel members of the rel/NF-kappaB
family that may also regulate HIV expression.
Effective start/end date7/1/915/31/95


  • National Institutes of Health: $214,664.00
  • National Institutes of Health
  • National Institutes of Health: $208,425.00


  • Medicine(all)

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