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 tra nsmembrane chemokine (7TM) receptor in addition to CD4 for efficient entry into cells. CCR5 and CXCR4 act as major co-receptors for non-syncytium-indu cing and syncytium-inducing strains respectively. We have examined the co-r eceptor requirement for HIV-1 infection of cells of macrophage lineage. Bot h CCR5 and CXCR4 can operate as functional co-receptors for infection in th ese cell types. Other co-receptors utilised by multi-co-receptor using stra ins of HIV-1, including CCR3 and STRL33, were not used for macrophage infec tion. HIV-2 and SIV strains, however, can replicate in both peripheral bloo d mononuclear cells (PBMCs) and other primary cell types such as fibroblast s independently of CCR5 or CXCR4. HIV co-receptors, particularly CCR5, will be major targets for new therapeu tics in this decade. We have therefore investigated different chemokines an d derivatives chat bind co-receptors for their capacity to inhibit HIV infe ction. These included derivatives of a CCR5 ligand, RANTES, with modified N -termini as well as Kaposi's sarcoma-associated herpesvirus-encoded chemoki nes 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, a minooxypentane or AOP-RANTES, was a particularly potent inhibitor of HIV in fection on PBMCs, macrophages and CCR5(+) cell lines and demonstrated the g reat promise of therapeutic strategies aimed at CCR5.