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Maraviroc Fully Inhibits Dual-R5 Virus in Dual/Mixed HIV-1 Infected Patients
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Reported by Jules Levin
17th CROI 2010 Feb 16-19 SF
Jori Symons*, S van Lelyveld, A Hoepelman, P van Ham, D de Jong, A Wensing, and M Nijhuis
Univ Med Ctr Utrecht, The Netherlands
Background: Currently, maraviroc (MVC) is only used in patients that harbor exclusively R5 tropic viruses. It was recently demonstrated in vitro that some of the dual-tropic viruses are much more efficient in using the CCR5 co-receptor (dual-R5), whereas others use the CXCR4 co-receptor more efficiently (dual-X4). Furthermore, maraviroc can suppress in vitro the replication of dual-R5 tropic viruses. We hypothesize that also in D/M HIV infected patients, maraviroc may suppress both the CCR5 and dual-R5 tropic viruses.
Methods: In 3 patients before start of MVC and during treatment, D/M co-receptor tropism was established by Trofile assay (input >1000 viral copies/mL), MT2 assay and genotypic V3 analysis. An in dept analysis of the MT2 virus culture was performed to obtain clonal isolates at each time point. U-373-MAGI cells expressing CD4+CCR5+, CD4+CXCR4+, and CD4+ as a control, were infected to determine co-receptor usage and preference. Peripheral blood mononuclear cells were used to determine MVC susceptibility and viral replication. In all experiments Ball and HXB2 were used as R5-tropic and X4-tropic control viruses, resp.
Results: The clonal isolates represented the patient's plasma viral populations as demonstrated by phylogenetic analysis, and were able to infect both CCR5 and CXCR4 bearing U373-MAGI cells. Baseline clones demonstrated clear CCR5 co-receptor preference (dual-R5) and were fully susceptible to MVC. In contrast, during maraviroc therapy the dual-R5 tropic viruses were replaced by more X4-tropic viruses (dual-X4), which could not be fully inhibited by MVC. The replication capacity of all viruses was comparable in peripheral blood mononuclear cells.
Conclusions: Here, we demonstrate that in the D/M classified patients MVC not only inhibits replication of R5 tropic viruses but may also inhibit dual-R5 tropic viruses. During continuous treatment dual-X4 viruses may be selected, which can not be inhibited by MVC. This indicates that MVC could play a role in treatment of D/M classified patients, especially in the background of a (partly) active backbone. Translation of these data into clinical practice warrants diagnostic tools which can discriminate dual R5 viruses from their dual X4 counterparts.
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