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Vol. 53, Issue 2, 340-345, February 1998
Institut de la Recerca de la SIDA Caixa, Hospital Universitari
Germans Trias i Pujol, Badalona, Spain (J.A.E., C.C., A.G., B.C.),
Rega
Institute for Medical Research, Katholieke Universiteit Leuven, 3000 Leuven, Belgium (J.A.E., D.S., P.C., M.W., C.P., Z.D., J.D., E.D.C.),
and
Aronex Pharmaceutical Corporation, The Woodlands, Texas (R.F.R.).
The human immunodeficiency virus (HIV) inhibitor AR177 (T30177,
Zintevir) has been identified as a potent inhibitor of HIV integrase
in vitro. The compound is currently the subject of
clinical phase I/II trials. However, the primary target for the
mechanism of action in vivo has not been identified
unequivocally. We have found that AR177 inhibits syncytium formation
between MOLT-4 cells and HUT-78 cells persistently infected with the
HIV-1IIIB or NL4-3 strain, at a 50% effective
concentration of 3 µg/ml, roughly 3-fold higher than the
concentration required to inhibit HIV replication. Furthermore, flow
cytometric analysis has shown that AR177 at 25 µg/ml interferes with
the binding of the monoclonal antibody 9284 (directed to the V3 loop of
gp120) on HIVIIIB-infected HUT-78 cells, pointing to
inhibition of virus binding or virus fusion as the mechanism of action
of AR177. To precisely characterize the site/target of intervention by
AR177, we have selected HIV-1 (NL4-3) strains resistant to AR177. The
binding of the AR177-resistant strain, unlike the parental HIV-1 NL4-3
strain, could not be inhibited by AR177. The resistant phenotype was
associated with the emergence of mutations in the gp120 molecule. DNA
sequence analysis revealed the presence of the K148E, Q278H, K290Q, and
F391I mutations and a deletion of 5 amino acids (FNSTW) at positions
364-368 in the V4 region of the resistant strain but not of the
wild-type HIV strain. Selection of resistant strains, although it takes
a relatively long time to develop, may also select for strains with
lower replicative capacity. No mutations were found in the integrase
enzyme gene. Our data argue against HIV integrase being the primary
target for the mechanism of anti-HIV action of AR177.
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