title: Effect of HIV-1 subtype and tropism on treatment with chemokine coreceptor entry inhibitors; overview of viral entry inhibition.
abstract: HIV-1 entry begins with viral envelope glycoprotein gp120 interacting with host-cell CD4 and an entry coreceptor (mainly chemokine receptors CCR5 or CXCR4). Inhibitors of particular coreceptors are being developed in order to exploit this step of cellular infection. However, effectiveness of these drugs requires matching of the administered therapeutic to coreceptor use by the viral variants infecting each patient. Patient viruses may use only CCR5 (R5), only CXCR4 (X4) or both (D/M). Most patients in early disease have R5 variants, with the presence of X4 variants increasing as disease progresses; the infecting subtype also affects the prevalence of X4 variants. Phenotypic, genotypic and clinical trial tests are in use to determine coreceptor utilization by HIV-1 variants, termed tropism, and to predict the response to entry inhibitors. Maraviroc is the only approved entry-coreceptor inhibitor and inhibits CCR5-gp120 interaction. Clinical trials of maraviroc in specific patient subgroups are elucidating the drug's role in contemporary clinical practice. Treatment failure to this and other CCR5 inhibitors has been shown to result from either outgrowth of X4 variants or through resistance mutations leading to R5 variants that are able to enter cells using drug-bound CCR5; thus, new entry inhibitors seek to circumvent this mechanism of resistance.
authors.affiliation: a Department of Internal Medicine & Infectious Diseases , Patras University General Hospital , Patras , Greece.
authors.forename: George
authors.initials: G
authors.lastname: Panos
authors.affiliation: a Department of Internal Medicine & Infectious Diseases , Patras University General Hospital , Patras , Greece.
authors.forename: Dionysios Christos
authors.initials: DC
authors.lastname: Watson
mesh_terms: D065100:CCR5 Receptor Antagonists / Q000627:therapeutic use*; D015704:CD4 Antigens / Q000378:metabolism; D003510:Cyclohexanes / Q000627:therapeutic use*; D018450:Disease Progression; D015699:HIV Envelope Protein gp120 / Q000378:metabolism*; D023581:HIV Fusion Inhibitors / Q000627:therapeutic use*; D015658:HIV Infections / Q000188:drug therapy; D015497:HIV-1 / Q000145:classification / Q000254:growth & development / Q000502:physiology*; D006801:Humans; D000077592:Maraviroc; D019713:Receptors, CCR5 / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D014230:Triazoles / Q000627:therapeutic use*; D056189:Viral Tropism / Q000187:drug effects / Q000502:physiology; D053586:Virus Internalization / Q000187:drug effects*
chemical_list: D065100:CCR5 Receptor Antagonists; C584933:CCR5 protein, human; D015704:CD4 Antigens; C527276:CXCR4 protein, human; D003510:Cyclohexanes; D015699:HIV Envelope Protein gp120; D023581:HIV Fusion Inhibitors; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D014230:Triazoles; C514793:gp120 protein, Human immunodeficiency virus 1; D000077592:Maraviroc
keywords: CCR5; CXCR4; maraviroc; phenotype; sequencing