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Mutations Outside V3 Loop May Further Resistance to CCR5 Drugs
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XVI International HIV Drug Resistance Workshop
June 12-16, 2007
Barbados
Mark Mascolini
Mutations in the coreceptor-binding region of HIV's envelope--but outside the V3 loop in envelope--may make virus resistant to CCR5 antagonists, according to results of a cell-based study by Monogram Biosciences [1].
Most CCR5 resistance research has focused on mutations in the V3 loop. To analyze the impact of potential mutations outside V3, Monogram investigators analyzed viruses resistant to the investigational CCR5 antagonist Schering C (SCH-C) that lacked major V3 loop mutations. They used classic serial passage experiments to select non-V3 mutations in peripheral blood mononuclear cells and PM-1 cells exposed to HIV-1 and increasing doses of SCH-C. (Schering is no longer developing SCH-C).
Viral variants generated in the serial passage experiments had reduced susceptibility to SCH-C when compared with pre-passage parental virus. Passaged virus with high-level resistance to SCH-C had 15 to 18 mutations in the gp120 envelope region and 2 to 3 changes in gp41. Only minor changes, or no changes at all, evolved in V3.
Monogram also built a series of chimeric envelopes incorporating various mutations to compare the impact of V3 mutations with those in non-V3 regions. These experiments indicated that mutations in V3 and the regions flanking V3 did not play a major role in resistance to SCH-C. In contrast, mutations in the C4 coreceptor-binding region of gp120 appeared to have a bigger impact on viral susceptibility to the CCR5 antagonist, especially when those mutations appeared with others in gp41 or gp120. Multiple mutations outside V3 had to emerge before virus became highly resistant to SCH-C.
Mutations in both the V3 and C4 regions decreased viral infectivity. But additional changes in V1 and V2 restored infectivity.
Monogram believes their findings suggest that HIV-1 can use non-V3 pathways to become resistant to CCR5 antagonists. But another workshop study of 4 people in whom maraviroc failed found that V3 mutations alone were usually necessary and sufficient to make HIV resistant to that drug [2].
Ultimately, suggested HIV entry expert Daniel Kuritzkes (Brigham and Women's Hospital, Boston), researchers will determine what drop in viral susceptibility to CCR5 antagonists yields high-level resistance to these drugs only when correlations with clinical response are made in a larger number of people. Still, Monogram's findings buttressed a recurring theme of this Resistance Workshop--resistance to CCR5 antagonists looks lots more oblique than resistance to other antiretrovirals.
References
1. Huang W, Wojcik L, Toma J, et al. Mutations in the coreceptor binding region of the
HIV-1 envelope confer resistance to the CCR5 inhibitor SCH-C (SCH 351125). Antiviral Therapy. 2007;12:S134. Abstract 121.
2. Mori J, Mosley M, Lewis M, et al. Characterization of maraviroc resistance in patients failing treatment with CCR5-tropic virus in MOTIVATE 1 and MOTIVATE 2. Antiviral Therapy. 2007;12:S12. Abstract 10.
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