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Cleavage Site Mutations in Patients with HIV Highly Resistant to Several Protease Inhibitors H. COTE1, Z. BRUMME1, K. HERTOGS2, B. LARDER2, and P. R. HARRIGAN*1.
1BC Ctr. for Excellence in HIV/AIDS, Vancouver, Canada; and 2Virco, N.V., Mechelen, Belgium Background: Compensatory mutations arise in HIV gag in association with protease inhibitor (PI) therapy. We wished to identify which changes in protease cleavage sites within and outside gag are specific to PI therapy and which sites are polymorphic.
Methods: We assessed the prevalence of mutations selected at ten protease cleavage sites (from gag to nef) in 28 people before and after exposure to PIs in individuals who had virus with >10 fold resistance to 3 or more available PIs. Results were compared to controls (matched for and pre- and post-therapy viral load and length of time on treatment) who never received PIs. The median fold resistance was: IND:29x, SAQ:30x, RIT:33x, NEL:41x as determined by phenotypic testing (Virco Antivirogram).
Results: As expected, cleavage site mutations arising during therapy in all sites in gag were much more common in individuals with PI cross-resistance. Changes flanking the NC were present in 50% and 36% of patients resistant to PIs vs 11% and 0% for patients not treated with PIs for P2/NC and NC/P1, respectively. The mutation QAN/F->QVN/F on the 5’ side of NC/p1 is the most common and specific adaptation to protease class resistance. The PR/RT, p51/p66, and p66/integrase cleavage sites were extremely highly conserved. Complete sequence data from nef is not available to date.
Conclusions: Multiple cleavage site mutations in gag are much more frequent in highly PI-resistant clinical isolates, with ~90% of this group having at least one gag site mutated. Surprisingly, simultaneous mutations outside the gag were very rare, even in this group.
Key Words: cleavage, HIV, protease
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