title: Increased CXCR4 use of HIV-1 subtype C identified by population sequencing in patients failing antiretroviral treatment compared with treatment-naive patients in Botswana.
abstract: HIV-1 uses the coreceptors CCR5 and/or CXCR4 for cell entry. Monotropic CCR5-using variants are found early in the infection while CXCR4-using variants may appear after progression to AIDS. CXCR4 use may consist of both monotropic and dualtropic viruses. The viral phenotype is important in evaluating the response to CCR5 inhibitors, a new class of antiviral drugs. The coreceptor use of HIV-1 was investigated using population sequencing in 24 patients from Botswana, carrying HIV-1 subtype C and failing antiretroviral treatment, while 26 treatment-naive patients acted as controls. Single genome sequencing was used to discern minor HIV-1 populations in the treatment-experienced group. The Geno2Pheno method was employed to predict the coreceptor use phenotype from HIV-1 env gp120 V3 DNA sequences. The glycan-charge model adjusted for subtype C was also used for phenotype prediction. The viral phenotype of population sequences was predicted using Geno2Pheno in 24/24 treatment-experienced patients, of whom eight (33%) were predicted to harbor CXCR4-using strains as compared to 2/26 in the treatment-naive group (p=0.03). Single genome sequencing generated 4-23 clones/patient in the treatment-experienced group. Altogether, 90/295 (31%) putative CXCR4-using clones were identified. In 10/24 (42%) treated patients at least one clone was predicted to be CXCR4-using, further increasing the amount of identified treatment-experienced patients with CXCR4 use. Although subtype C is usually associated with comparatively little CXCR4 use, the frequency of CXCR4 use in treatment-experienced patients with subtype C can be higher, which may have implications for the administration of CCR5 inhibitors in this patient group.
authors.affiliation: 1 Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet , Stockholm, Sweden .
authors.forename: Lotta Pramanik
authors.initials: LP
authors.lastname: Sollerkvist
authors.forename: Simani
authors.initials: S
authors.lastname: Gaseitsiwe
authors.forename: Madisa
authors.initials: M
authors.lastname: Mine
authors.forename: Gaseene
authors.initials: G
authors.lastname: Sebetso
authors.forename: Thongbotho
authors.initials: T
authors.lastname: Mphoyakgosi
authors.forename: Thabo
authors.initials: T
authors.lastname: Diphoko
authors.forename: Max
authors.initials: M
authors.lastname: Essex
authors.forename: Anneka
authors.initials: A
authors.lastname: Ehrnst
mesh_terms: D000328:Adult; D044966:Anti-Retroviral Agents / Q000627:therapeutic use*; D001902:Botswana; D024882:Drug Resistance, Viral; D005260:Female; D005838:Genotype; D015699:HIV Envelope Protein gp120 / Q000235:genetics*; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D015497:HIV-1 / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D019718:Receptors, CXCR4 / Q000378:metabolism*; D015728:Receptors, HIV / Q000378:metabolism; D017422:Sequence Analysis, DNA; D017211:Treatment Failure; D056189:Viral Tropism
chemical_list: D044966:Anti-Retroviral Agents; C527276:CXCR4 protein, human; D015699:HIV Envelope Protein gp120; D019718:Receptors, CXCR4; D015728:Receptors, HIV; C514793:gp120 protein, Human immunodeficiency virus 1