J Virol, June 1998, p. 4765-4774, Vol. 72, No. 6
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, Republic of China
Received 15 October 1997/Accepted 17 February 1998
It has been previously shown that a proline substitution for any of
the conserved leucine or isoleucine residues located in the leucine
zipper-like heptad repeat sequence of human immunodeficiency virus type
1 (HIV-1) gp41 renders viruses noninfectious and envelope (Env) protein
unable to mediate membrane fusion (S. S.-L. Chen, C.-N. Lee, W.-R.
Lee, K. McIntosh, and T.-M. Lee, J. Virol. 67:3615-3619, 1993;
S. S.-L. Chen, J. Virol. 68:2002-2010, 1994). To understand whether these variants could act as trans-dominant
inhibitory mutants, the ability of these mutants to inhibit wild-type
(wt) virus infectivity was examined. Comparable amounts of cell- and virion-associated gag gene products as well as
virion-associated gp41 were found in transfection with wt or mutant
HIV-1 provirus. Viruses obtained from coexpression of wt provirus with
mutant 566 or 580 provirus inhibited more potently the production of infectious virus than did viruses generated from cotransfection of wt
provirus with other mutant proviruses. Nevertheless, all viruses
produced from mixed transfection showed decreased infectivity compared
with that of the wt virus when a multinuclear-activation
-galactosidase induction assay was performed. The ability of wt Env
to induce cytopathic effects was inhibited by coexpression with mutant
Env. Coexpression of mutants inhibited the ability of the wt protein to
mediate virus-to-cell transmission, as demonstrated by an env
trans-complementation assay with a defective HIV-1 proviral vector. These observations indicated that mutant Env, per se, interferes with wt Env function. Moreover, cotransfection of wt and
mutant proviruses produced amounts of cell- and virion-associated gag gene products comparable to those produced by
transfection of wt provirus. Similar amounts of gp41 were also found in
virions generated from wt-mutant cotransfection as well as from wt
transfection alone. These results indicated that the inhibitory effect
conferred by mutants on the wt virus infectivity does not involve the
late steps of Gag protein assembly and budding, but they suggest that the wt and mutant Env proteins form a dysfunctional hetero-oligomer which is impaired in an early step of the virus replication cycle. Our
study demonstrates that mutations in the HIV-1 gp41 leucine zipper-like
heptad repeat sequence dominantly inhibit infectious virus production.
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