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Viral Resistance to the HIV-1 Maturation Inhibitor Bevirimat in the Context of a Protease that Confers Resistance to Protease Inhibitors
Catherine Adamson*1, K Waki1, S Ablan1, K Salzwedel2, and E Freed1
1NCI-Frederick, MD, US and 2Panacos Pharma, Inc, Gaithersburg, MD, US
Background: The maturation inhibitor bevirimat (PA-457)
potently inhibits HIV-1 replication by blocking Gag processing at the CA-SP1
cleavage site. We previously isolated a panel of 6 PA-457-resistant mutants in
vitro. The mutations map to the CA/SP1 junction in CA or SP1 (CA-H226Y,
L231M, L231F; SP1-A1V, A3V, A3T). Since PA-457 will likely be used clinically
in protease inhibitor (PI) -experienced patients, we examined the impact of
mutations that confer resistance to PI on the evolution of PA-457 resistance.
Methods: We introduced all of our PA-457-resistance
mutations into a molecular clone encoding a PI-resistant Protease and evaluated
virus replication, Gag processing, and virus maturation both in the presence
and absence of PA-457. Selection experiments in vitro were performed in
the presence of PA-457 using the PI resistant clone to examine acquisition of
PA-457 resistance in the context of the mutant PR.
Results: Biochemical analysis demonstrated global
defects in Gag processing in the presence of the PI resistant mutations
independent of the sequence at the CA-SP1 junction or the presence of PA-457.
As a likely consequence of the global processing defects, modest delays in
virus replication were observed for the PI resistant clone in the context of wild
type Gag or fit PA-457-resistance mutations either in the presence or absence
of PA-457. For replication-impaired PA-457-resistant Gag mutants, combination
with the PI-resistant PR abolished virus replication. PA-457 resistance in the
PI-resistant context took significantly longer to emerge than in the context of
wild type PR.
Conclusions: Understanding the evolution of
resistance to PA-457 is highly significant as this compound is currently
undergoing phase IIb clinical trials in HIV-1-infected patients. The nature of
PA-457 resistance arising in the context of both wild type and mutant PR
elucidates the interplay between mutations in PR and the CA/SP1 cleavage site
and may help to predict the types of mutations that are more likely to arise in
vivo. The data presented in this study suggest that PI-resistant mutants
may be less likely than wild type isolates to develop PA-457 resistance.
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