title: On the Physicochemical and Structural Modifications Associated with HIV-1 Subtype B Tropism Transition.
abstract: HIV-1 enters immune cells via binding the viral envelope to a host cell CD4 receptor, and then a secondary co-receptor, usually CCR5 (R5) or CXCR4 (X4), and some HIV can utilize both co-receptors (R5X4). Although a small set of amino-acid properties such as charge and sequence length applied to HIV-1 envelope V3 loop sequence data can be used to predict co-receptor usage, we sought to expand the fundamental understanding of the physiochemical basis of tropism by analyzing many, perhaps less obvious, amino-acid properties over a diverse array of HIV sequences. We examined 74 amino-acid physicochemical scales over 1,559 V3 loop sequences with biologically tested tropisms downloaded from the Los Alamos HIV sequence database. Linear regressions were then calculated for each feature relative to three tropism transitions (R5→X4; R5→R5X4; R5X4→X4). Independent correlations were rank ordered to determine informative features. A structural analysis of the V3 loop was performed to better interpret these findings relative to HIV tropism states. Similar structural changes are required for R5 and R5X4 to transition to X4, thus suggesting that R5 and R5X4 types are more similar than either phenotype is to X4. Overall, the analysis suggests a continuum of viral tropism that is only partially related to charge; in fact, the analysis suggests that charge modification may be primarily attributed to decreased R5 usage, and further structural changes, particularly those associated with β-sheet structure, are likely required for full X4 usage.
authors.affiliation: 1 Bioinfoexperts, LLC , Thibodaux, Louisiana.
authors.forename: Susanna L
authors.initials: SL
authors.lastname: Lamers
authors.affiliation: 2 Natural Selection, Inc. , San Diego, California.
authors.forename: Gary B
authors.initials: GB
authors.lastname: Fogel
authors.affiliation: 2 Natural Selection, Inc. , San Diego, California.
authors.forename: Enoch S
authors.initials: ES
authors.lastname: Liu
authors.affiliation: 3 Department of Pathology and Laboratory Medicine, University of Florida , Gainesville, Florida.
authors.forename: Marco
authors.initials: M
authors.lastname: Salemi
authors.affiliation: 4 Department of Laboratory Medicine, Pathology, and Medicine, and the AIDS and Cancer Specimen Resource, University of California , San Francisco, California.
authors.forename: Michael S
authors.initials: MS
authors.lastname: McGrath
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D015704:CD4 Antigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D030541:Databases, Genetic; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D056004:Molecular Dynamics Simulation; D010641:Phenotype; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D000072757:Protein Conformation, beta-Strand; D054730:Protein Interaction Domains and Motifs; D019713:Receptors, CCR5 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D055672:Static Electricity; D013601:T-Lymphocytes / Q000821:virology*; D013816:Thermodynamics; D056189:Viral Tropism / Q000235:genetics*; D053585:Virus Attachment
chemical_list: C584933:CCR5 protein, human; D015704:CD4 Antigens; C527276:CXCR4 protein, human; D015699:HIV Envelope Protein gp120; D019713:Receptors, CCR5; D019718:Receptors, CXCR4