Xy. Qian et al., NEW APPROACH FOR INHIBITING REV FUNCTION AND HIV-1 PRODUCTION USING THE INFLUENZA-VIRUS NS1 PROTEIN, Proceedings of the National Academy of Sciences of the United Statesof America, 93(17), 1996, pp. 8873-8877
The Rev protein of HIV-1, which facilitates the nuclear export of HIV-
1 pre-mRNAs, has been a target for antiviral therapy. Here we describe
a new strategy for inhibiting Rev function and HIV-1 replication, In
contrast to previous approaches, we use a wild-type rather than a muta
nt Rev protein and covalently link this Rev sequence to the NS1 protei
n of influenza A virus, a protein that inhibits the nuclear export of
mRNAs. The NS1 protein contains an RNA-binding domain mutation (RM), s
o that the only functional RNA-binding domain in the chimeric protein
(NS1RM-Rev) is in the Rev protein sequence. In the presence of the NS1
RM-Rev chimeric protein, HIV-1 pre-mRNAs were retained in, rather than
exported from, the nucleus. In addition, this chimeric protein effect
ively inhibited Rev function in trans in transfection experiments and
effectively inhibited the production of HIV-1 in tissue culture cells
transfected with an infectious molecular clone of HIV-1 DNA. The inhib
itory activities of the NS1RM-Rev chimera were at least equivalent to
those of the Rev M10 mutant protein, which has been considered to be t
he prototype trans inhibitor of Rev function and is currently in phase
I clinical trials for the treatment of AIDS patients. we discuss (i)
the potential for increasing the inhibitory activity of NS1-Rev chimer
as against HIV-I and (ii) the need for additional studies to evaluate
these chimeras for the treatment of AIDS.