Enhanced Inhibition of Human Immunodeficiency Virus Type 1 by Met-Stromal-Derived Factor 1β Correlates with Down-Modulation of CXCR4

Abstract

CXCR4 is a chemokine receptor used by some strains of HIV-1 as an entry coreceptor in association with cell surface CD4 on human cells. In human immunodeficiency virus type 1 (HIV-1)-infected individuals, the appearance of viral isolates with a tropism for CXCR4 (T tropic) has been correlated with late disease progression. The presumed natural ligands for CXCR4 are SDF-1α and SDF-1β, which are proposed to play a role in blocking T-tropic HIV-1 cell entry. Here, we demonstrate that addition of an N-terminal methionine residue to SDF-1β (Met-SDF-1β) results in a dramatically enhanced functional activity compared to that of native SDF-1β. Equivalent concentrations of Met-SDF-1β are markedly more inhibitory for T-tropic HIV-1 replication than SDF-1β. A comparison of the biological activities of these two forms of SDF-1β reveals that Met-SDF-1β induces a more pronounced intracellular calcium flux yet binds with slightly lower affinity to CXCR4 than SDF-1β. Down-modulation of CXCR4 is similar after exposure of cells to either chemokine form for 2 h. However, after a 48-h incubation, the surface expression of CXCR4 is much lower for cells treated with Met-SDF-1β. The enhanced blocking of T-tropic HIV-1 by Met-SDF-1β appears to be related to prolonged CXCR4 down-modulation.