Co-receptor use by HIV and inhibition of HIV infection by chemokine receptor ligands.
Human and simian immunodeficiency viruses (HIV and SIV) require a seven transmembrane chemokine (7TM) receptor in addition to CD4 for efficient entry into cells. CCR5 and CXCR4 act as major co-receptors for non-syncytium-inducing and syncytium-inducing strains respectively. We have examined the co-receptor requirement for HIV-1 infection of cells of macrophage lineage. Both CCR5 and CXCR4 can operate as functional co-receptors for infection in these cell types. Other co-receptors utilised by multi-co-receptor-using strains of HIV-1, including CCR3 and STRL33, were not used for macrophage infection. HIV-2 and SIV strains, however, can replicate in both peripheral blood mononuclear cells (PBMCs) and other primary cell types such as fibroblasts independently of CCR5 or CXCR4. HIV co-receptors, particularly CCR5, will be major targets for new therapeutics in this decade. We have therefore investigated different chemokines and derivatives that bind co-receptors for their capacity to inhibit HIV infection. These included derivatives of a CCR5 ligand, RANTES, with modified N-termini as well as Kaposi's sarcoma-associated herpesvirus-encoded chemokines that bind a wide range of co-receptors, including CCR5, CXCR4, CCR3 and CCR8, as well as the orphan 7TM receptors GPR1 and STRL33. One compound, aminooxypentane or AOP-RANTES, was a particularly potent inhibitor of HIV infection on PBMCs, macrophages and CCR5+ cell lines and demonstrated the great promise of therapeutic strategies aimed at CCR5.
Simmons
G
G
Wohl Virion Centre, Department of Molecular Pathology, Windeyer Institute of Medical Sciences, University College London, UK. grahamsimmons@hotmail.com
Reeves
J D
JD
Hibbitts
S
S
Stine
J T
JT
Gray
P W
PW
Proudfoot
A E
AE
Clapham
P R
PR
D018925:Chemokines / Q000276:immunology; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D015498:HIV-2 / Q000276:immunology*; D006801:Humans; D008024:Ligands; D019707:Receptors, Chemokine / Q000276:immunology*; D015728:Receptors, HIV / Q000276:immunology*
D018925:Chemokines; D008024:Ligands; D019707:Receptors, Chemokine; D015728:Receptors, HIV