title: 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.
authors.affiliation: 1 Viral Evolution and Transmission Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute , Milan, Italy .
authors.forename: Mariangela
authors.initials: M
authors.lastname: Cavarelli
authors.forename: Lara
authors.initials: L
authors.lastname: Mainetti
authors.forename: Angela Rosa
authors.initials: AR
authors.lastname: Pignataro
authors.forename: Alba
authors.initials: A
authors.lastname: Bigoloni
authors.forename: Monica
authors.initials: M
authors.lastname: Tolazzi
authors.forename: Andrea
authors.initials: A
authors.lastname: Galli
authors.forename: Silvia
authors.initials: S
authors.lastname: Nozza
authors.forename: Antonella
authors.initials: A
authors.lastname: Castagna
authors.forename: Michela
authors.initials: M
authors.lastname: Sampaolo
authors.forename: Enzo
authors.initials: E
authors.lastname: Boeri
authors.forename: Gabriella
authors.initials: G
authors.lastname: Scarlatti
mesh_terms: D000293:Adolescent; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods; D018791:CD4 Lymphocyte Count; D018946:Chemokine CCL5 / Q000502:physiology; D003510:Cyclohexanes / Q000627:therapeutic use; D000069454:Darunavir; D024921:Drug Resistance, Multiple, Viral; D015699:HIV Envelope Protein gp120 / Q000235:genetics; D054303:HIV Reverse Transcriptase / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage / Q000627:therapeutic use; D006801:Humans; D000077592:Maraviroc; D010078:Oxazines; D010446:Peptide Fragments / Q000235:genetics; D010802:Phylogeny; D010879:Piperazines; D011728:Pyridones; D019713:Receptors, CCR5 / Q000502:physiology; D019718:Receptors, CXCR4 / Q000502:physiology; D019438:Ritonavir / Q000008:administration & dosage / Q000627:therapeutic use; D013449:Sulfonamides / Q000008:administration & dosage / Q000627:therapeutic use; D014230:Triazoles / Q000627:therapeutic use; D019562:Viral Load / Q000187:drug effects; D056189:Viral Tropism / Q000187:drug effects; D000099226:Dolutegravir
chemical_list: D019380:Anti-HIV Agents; D018946:Chemokine CCL5; D003510:Cyclohexanes; D000069454:Darunavir; D015699:HIV Envelope Protein gp120; D054303:HIV Reverse Transcriptase; D006575:Heterocyclic Compounds, 3-Ring; D000077592:Maraviroc; D010078:Oxazines; D010446:Peptide Fragments; D010879:Piperazines; D011728:Pyridones; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D019438:Ritonavir; D013449:Sulfonamides; D014230:Triazoles; D000099226:Dolutegravir; C584933:CCR5 protein, human; C527276:CXCR4 protein, human; C059762:HIV envelope protein gp120 (305-321)