Modelling binding between CCR5 and CXCR4 receptors and their ligands suggests the surface electrostatic potential of the co-receptor to be a key player in the HIV-1 tropism.
BACKGROUND
CCR5 and CXCR4 are the two membrane-standing proteins that, along with CD4, facilitate entry of HIV particles into the host cell. HIV strains differ in their ability to utilize either CCR5 or CXCR4, and this specificity, also known as viral tropism, is largely determined by the sequence of the V3 loop of the viral envelope protein gp120.


RESULTS
With statistical and docking approaches we have computationally analyzed binding preferences of CCR5 and CXCR4 to both V3 loop sequences of virus strains of different tropism and endogenous ligands.


CONCLUSIONS
We conclude that the tropism cannot be satisfactorily explained by amino-acid interactions alone, and suggest a two-step mechanism, by which initial coreceptor selection and approach of the ligand to the binding pocket is dominated by charge and glycosylation pattern of the viral envelope.
Department for Computational Biology and Applied Algorithmics, Max Planck Institute for Informatics, Campus E1 4, Saarbrücken 66123, Germany. kalinina@mpi-inf.mpg.de.
Olga V
OV
Kalinina
Nico
N
Pfeifer
Thomas
T
Lengauer
D015699:HIV Envelope Protein gp120 / Q000378:metabolism*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D056004:Molecular Dynamics Simulation; D019713:Receptors, CCR5 / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism*; D015728:Receptors, HIV / Q000378:metabolism*; D055672:Static Electricity; D056189:Viral Tropism; D053585:Virus Attachment
C584933:CCR5 protein, human; C527276:CXCR4 protein, human; D015699:HIV Envelope Protein gp120; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D015728:Receptors, HIV