Mechanisms of failure to CCR5 inhibitors is not explained by mutation in the V3 loop, cross-resistance between CCR5 inhibitors is likely

Simon Collins, HIV i-Base

In vivo resistance to CCR5 inhibitors is not clearly understood. It does not seem to follow loss of sensitivity predicted by in vitro changes in the V3 loop and is limited by the small number of patient with clinical failure. Studies at the conference provided data on both maraviroc and vicriviroc.

Julie Mori and colleagues from Pfizer maraviroc looked at phenotypic and genotypic markers in paired baseline and on-treatment samples from 37 patients (12 clones from each patients) with virological failure in the MOTIVATE studies. [1]

Criteria for further investigation were based on IC50 fold changes compared to either reference or baseline virus, or a plateau (<95%) in maximal percentage inhibition (MPI) – one of the new methods to investigate lack of CCR5-inhibitor response (and which had characterised in vitro resistance over changes in IC50).

No changes in MPI were found at baseline, though this was found on study in 4/12 failures patients in maraviroc arms and in one placebo patient. In general, patients failing maraviroc showed no increase in IC50, except for one patient who showed a 3-fold shift from baseline.

Changes in the V3 loop were shown in 6/12 patients with virological failure (including one patient on placebo). Mutation patterns were distinct for each patient although mutations at position 13 or 26 in the V3 loop were present in 5/6 patients.

Site-directed mutagenesis presented for four patients suggested that V3 mutations were sufficient at baseline and necessary at treatment failure for resistance to CCR5 antagonists.

In randomly selected samples from 8 patients with virological failure in the dose-finding Phase II ACTG 5211 vicriviroc study (2 patients from each of the placebo, 5mg, 10mg and 15mg VVC arms), V3 loop mutations were found in 5 patients. [2]

However, those mutations did not show any consistent reduction in viral susceptibility to the vicriviroc (shown by changes in IC50 through to week 24) with a maximum increase compared to control of 2.8 fold. V3 loop changes in 4/4 patients in the 5mg and 10mg arms were not found in the placebo or 15mg arms.

Additional sampling on one patients from the 10mg arm of the study, who showed reduced susceptibility to vicriviroc (and progressive loss of CCR5 inhibition) showed emergence of V3 loop mutations. Five months after discontinuing vivroviroc, this patient showed a return to R5 virus, baseline V3 sequences and phenotypic sensitivity.

Finally, Wei Huang and colleagues from Monogram, manufacturers of the Trofile tropism assay used in current CCR5 inhibitor studies, presented results from resistance to vicriviroc derived from in vitro passaging that suggested high-level resistance may be dependent on mutations that occur outside of V3. [3]

In this case, escape viruses with high level resistance contained 15-16 amino acid changes in gp120 and 2-3 changes in gp41, with only minor changes in the V3 loop.


  1. 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.
  2. Tsibris AMN, Gulick RM, Su Z, et al. In vivo emergence of HIV-1 resistance to the CCR5 antagonist vicriviroc: findings from ACTG A5211. Antiviral Therapy. 2007;12:S15. Abstract 13.
  3. 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.

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