[AEGiS-1HIVDRTS: 19] Drug resistance during indinavir therapy is caused by mutations in the protease gene and in its Gag substrate cleavage sites

1st International Workshop on HIV Drug Resistance & Treatment Strategies

25-28 June 1997, St. Petersburg, Florida, USA

DRUG RESISTANCE DURING INDINAVIR THERAPY IS CAUSED BY MUTATIONS IN THE PROTEASE GENE AND IN ITS GAG SUBSTRATE CLEAVAGE SITES

Antiviral Therapy 1997;2 (Suppl 5):13 (abstract no. 19)

Y-M Zhang¹, H Imamichi¹, T Imamichi¹, HC Lane², J Falloon², MB Vasudevachari¹ and NP Salzman¹
¹SAIC Frederick, NCI-FCRDC, Frederick, Maryland; and ²NIAID, Bethesda, Maryland, USA

Two different responses to therapy were observed in a group of patients receiving the protease inhibitor indinavir. In one, suppression of HIV replication occurred and persisted for 2 years (bDNA <500 HIV-1 RNA copies/ml). In the remaining six patients, a rebound in plasma virus levels followed the initial sharp decline observed at the start of therapy. This was associated with the emergence of protease drug-resistant variants. Sequence analysis of the protease gene during the course of therapy in those patients revealed a sequential acquisition of protease mutations at amino acids 46, 54, 71, 82, 89 and 90. In the six patients in this group, there was also an identical mutation in the gag p7/p1 protease cleavage site. In three of the six patients, this change was seen as early as 6-10 weeks after the start of therapy. In one patient, a second mutation occurred at the p1/p6 cleavage site but it appeared 18 weeks after the time of appearance of the p7/p1 mutation.

To assess the role of the gag site mutations in the emergence of drug-resistant HIV-1 variants, recombinant viruses containing two or three mutations in the protease gene were constructed either with mutations at the p7/p1 cleavage site or with wild-type gag sequences. When recombinant HIV-1 containing protease mutations at 46 and 82 was grown in MT-2 cells, there was a 70% reduction in its rate of replication compared to wild-type virus. Introduction of an additional mutation at the gag p7/p1 protease cleavage site compensated for the partially defective protease gene. Similarly, rates of replication of viruses with mutations M46L, I54V and V82A in protease were enhanced when combined with mutations in the gag p7/p1 and gag p1/p6 cleavage sites. This was seen in the presence and in the absence of indinavir.

Optimum rates of virus replication require protease cleavage of precursor polyproteins. A mutation in a cleavage site that enhanced cleavage by the mutant protease would confer on that virus a significant growth advantage, and may explain the uniform emergence of viruses with alterations at the p7/p1 cleavage site.

This is the first report of the emergence of mutations in the gag p7/p1 protease cleavage sites in patients receiving protease therapy and identifies this change as an important determinant of HIV-1 resistance in patient populations.

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1997-06-25
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