CLEAVAGE OF THE MURINE LEUKEMIA-VIRUS TRANSMEMBRANE ENV PROTEIN BY HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 PROTEASE - TRANSDOMINANT INHIBITION BY MATRIX MUTATIONS
Re. Kiernan et Eo. Freed, CLEAVAGE OF THE MURINE LEUKEMIA-VIRUS TRANSMEMBRANE ENV PROTEIN BY HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 PROTEASE - TRANSDOMINANT INHIBITION BY MATRIX MUTATIONS, Journal of virology (Print), 72(12), 1998, pp. 9621-9627
We have identified mutations in the human immunodeficiency virus type
1 (HIV-1) matrix protein (MA) which block infectivity of virions pseud
otyped with murine leukemia virus (MuLV) envelope (Env) glycoproteins
without affecting infectivity conferred by HIV-1 Env or vesicular stom
atitis virus G glycoproteins. This inhibition is very potent and displ
ays a strong transdominant effect; infectivity is reduced more than 10
0-fold when wild-type and mutant molecular clones are cotransfected at
a 1:I ratio. This phenomenon is observed with both ecotropic and amph
otropic MuLV Env. The MA mutations do not affect the incorporation of
MuLV Env into virions. We demonstrate that in HIV-I virions pseudotype
d with MuLV Env, the HIV-I protease (PR) efficiently catalyzes the cle
avage of the p15(E) tansmembrane (TM) protein to p12(E). Immunoprecipi
tation analysis of pseudotyped virions reveals that the mutant MA bloc
ks this HIV-1 PR-mediated cleavage of MuLV TM. Furthermore, the transd
ominant inhibition exerted by the mutant MA on wild-type infectivity c
orrelates with the relative level of p15(E) cleavage. Consistent,vith
the hypothesis that abrogation of infectivity imposed by the mutant MA
is due to inhibition of p15(E) cleavage, mutant virions are significa
ntly more infectious when pseudotyped with a truncated p12(E) form of
MuLV Env. These results indicate that HIV-1 Gag sequences can influenc
e the viral PR-mediated processing of the MuLV TM Env protein p15(E).
These findings have implications for the development of HIV-1-based re
troviral vectors pseudotyped with MuLV Env, since p15(E) cleavage is e
ssential far activating membrane fusion and virus infectivity.