Complexity and Dynamics of HIV-1 Chemokine Receptor Usage in a Multidrug-Resistant Adolescent

Abstract

Maraviroc (MVC) is licensed in clinical practice for patients with R5 virus and virological failure; however, in anecdotal reports, dual/mixed viruses were also inhibited. We retrospectively evaluated the evolution of HIV-1 coreceptor tropism in plasma and peripheral blood mononuclear cells (PBMCs) of an infected adolescent with a CCR5/CXCR4 Trofile profile who experienced an important but temporary immunological and virological response during a 16-month period of MVC-based therapy. Coreceptor usage of biological viral clones isolated from PBMCs was investigated in U87.CD4 cells expressing wild-type or chimeric CCR5 and CXCR4. Plasma and PBMC-derived viral clones were sequenced to predict coreceptor tropism using the geno2pheno algorithm from the V3 envelope sequence and pol gene-resistant mutations. From start to 8.5 months of MVC treatment only R5X4 viral clones were observed, whereas at 16 months the phenotype enlarged to also include R5 and X4 clones. Chimeric receptor usage suggested the preferential usage of the CXCR4 coreceptor by the R5X4 biological clones. According to phenotypic data, R5 viruses were susceptible, whereas R5X4 and X4 viruses were resistant to RANTES and MVC in vitro. Clones at 16 months, but not at baseline, showed an amino acidic resistance pattern in protease and reverse transcription genes, which, however, did not drive their tropisms. The geno2pheno algorithm predicted at baseline R5 viruses in plasma, and from 5.5 months throughout follow-up only CXCR4-using viruses. An extended methodological approach is needed to unravel the complexity of the phenotype and variation of viruses resident in the different compartments of an infected individual. The accurate evaluation of the proportion of residual R5 viruses may guide therapeutic intervention in highly experienced patients with limited therapeutic options.

Achieving virological control in pan-resistant HIV-1 infection: A case series

“…Because of the very limited therapeutical options, we added MVC to target residual R5 variants and maximize the antiviral activity of OBR. 15 Case 2 viremia reached values permanently < 100 copies/mL from week 4. A transient virological rebound was observed between week 24 and 34 (3690 copies/mL), correlating with ENF interruption because of reduced tolerance.…”

CCR5/CXCR4 Dual Antagonism for the Improvement of HIV Infection Therapy

“…Antiviral effects of Maraviroc were investigated on U87.CD4 cells expressing wild type or chimeric CCR5 and CXCR4. Furthermore, a direct influence of the drug was observed on the onset of resistance in infected patients [24]. Phase II clinical studies confirmed the susceptibility to Maraviroc of dual mixed tropic viruses, with an activity even higher than that recorded towards pure R5 strains [25].…”