title: An expanded model of HIV cell entry phenotype based on multi-parameter single-cell data.
abstract: BACKGROUND
  Entry of human immunodeficiency virus type 1 (HIV-1) into the host cell involves interactions between the viral envelope glycoproteins (Env) and the cellular receptor CD4 as well as a coreceptor molecule (most importantly CCR5 or CXCR4). Viral preference for a specific coreceptor (tropism) is in particular determined by the third variable loop (V3) of the Env glycoprotein gp120. The approval and use of a coreceptor antagonist for antiretroviral therapy make detailed understanding of tropism and its accurate prediction from patient derived virus isolates essential. The aim of the present study is the development of an extended description of the HIV entry phenotype reflecting its co-dependence on several key determinants as the basis for a more accurate prediction of HIV-1 entry phenotype from genotypic data.
  
  
  RESULTS
  Here, we established a new protocol of quantitation and computational analysis of the dependence of HIV entry efficiency on receptor and coreceptor cell surface levels as well as viral V3 loop sequence and the presence of two prototypic coreceptor antagonists in varying concentrations. Based on data collected at the single-cell level, we constructed regression models of the HIV-1 entry phenotype integrating the measured determinants. We developed a multivariate phenotype descriptor, termed phenotype vector, which facilitates a more detailed characterization of HIV entry phenotypes than currently used binary tropism classifications. For some of the tested virus variants, the multivariant phenotype vector revealed substantial divergences from existing tropism predictions. We also developed methods for computational prediction of the entry phenotypes based on the V3 sequence and performed an extrapolating calculation of the effectiveness of this computational procedure.
  
  
  CONCLUSIONS
  Our study of the HIV cell entry phenotype and the novel multivariate representation developed here contributes to a more detailed understanding of this phenotype and offers potential for future application in the effective administration of entry inhibitors in antiretroviral therapies.
authors: Department of Computational Biology and Applied Algorithmics, Max Planck for Computer Sciences, Campus E1 4 66123, Saarbrücken, Germany.
authors: Katarzyna
authors: K
authors: Bozek
authors: Manon
authors: M
authors: Eckhardt
authors: Saleta
authors: S
authors: Sierra
authors: Maria
authors: M
authors: Anders
authors: Rolf
authors: R
authors: Kaiser
authors: Hans-Georg
authors: HG
authors: Kräusslich
authors: Barbara
authors: B
authors: Müller
authors: Thomas
authors: T
authors: Lengauer
mesh_terms: D000595:Amino Acid Sequence; D001596:Benzylamines; D065100:CCR5 Receptor Antagonists; D019295:Computational Biology; D000080027:Cyclams; D003510:Cyclohexanes / Q000494:pharmacology; D005822:Genetic Vectors; D057809:HEK293 Cells; D023581:HIV Fusion Inhibitors / Q000494:pharmacology; D015658:HIV Infections / Q000378:metabolism / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology*; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D000077592:Maraviroc; D008954:Models, Biological; D008969:Molecular Sequence Data; D015999:Multivariate Analysis; D010641:Phenotype; D019713:Receptors, CCR5 / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014230:Triazoles / Q000494:pharmacology; D053586:Virus Internalization
chemical_list: D001596:Benzylamines; D065100:CCR5 Receptor Antagonists; C527276:CXCR4 protein, human; D000080027:Cyclams; D003510:Cyclohexanes; D023581:HIV Fusion Inhibitors; D006571:Heterocyclic Compounds; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D014230:Triazoles; D000077592:Maraviroc; C088327:plerixafor