Maraviroc is able to inhibit dual-R5 viruses in a dual/mixed HIV-1-infected patient

Abstract

Maraviroc is the first licensed chemokine co-receptor 5 (CCR5) co-receptor antagonist in clinical practice. It is currently being used in patients harbouring exclusively CCR5-tropic virus. The objective of the study was to investigate the impact of maraviroc on viruses with different co-receptor preferences in a patient with a dual/mixed (D/M) infection. We present a case report of an HIV-1 patient infected with a D/M virus population. Co-receptor tropism was determined by phenotypic and genotypic tests. Biological clones from pre- and post-maraviroc therapy were generated. Tropism of these infectious clones was investigated in U373-MAGI cells expressing CD4+ CCR5+ or CD4+ CXCR4+. Maraviroc susceptibility and viral replication were determined using donor peripheral blood mononuclear cells (PBMCs). In-depth clonal genotypic analysis revealed the presence of both R5-tropic variants and X4-tropic viruses before the start of maraviroc. During maraviroc therapy all R5-predicted viruses were suppressed. Phenotypic analyses revealed that all biological clones before maraviroc therapy could infect both CCR5- and CXCR4-bearing U373-MAGI cells, demonstrating dual tropism. The baseline biological clones preferentially infected the CCR5 cell line and were fully susceptible to maraviroc in PBMCs (dual-R5). In contrast, during maraviroc therapy the dual-R5-tropic viruses were replaced by more X4-tropic viruses (dual-X4), which could not be inhibited by maraviroc. This case report demonstrates that dual-tropic viruses, capable of using both co-receptors in phenotypic assays, can be inhibited by maraviroc if they have a CCR5 co-receptor preference in vivo.