Enhanced inhibition of human immunodeficiency virus type 1 by Met-stromal-derived factor 1beta correlates with down-modulation of CXCR4.
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-1alpha and SDF-1beta, 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-1beta (Met-SDF-1beta) results in a dramatically enhanced functional activity compared to that of native SDF-1beta. Equivalent concentrations of Met-SDF-1beta are markedly more inhibitory for T-tropic HIV-1 replication than SDF-1beta. A comparison of the biological activities of these two forms of SDF-1beta reveals that Met-SDF-1beta induces a more pronounced intracellular calcium flux yet binds with slightly lower affinity to CXCR4 than SDF-1beta. 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-1beta. The enhanced blocking of T-tropic HIV-1 by Met-SDF-1beta appears to be related to prolonged CXCR4 down-modulation.
Yang
O O
OO
AIDS Research Center and Infectious Disease Unit, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.
Swanberg
S L
SL
Lu
Z
Z
Dziejman
M
M
McCoy
J
J
Luster
A D
AD
Walker
B D
BD
Herrmann
S H
SH
D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism / Q000494:pharmacology*; D015536:Down-Regulation; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008715:Methionine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008969:Molecular Sequence Data; D019718:Receptors, CXCR4 / Q000032:analysis / Q000187:drug effects*
D019380:Anti-HIV Agents; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D019718:Receptors, CXCR4; C119139:methionine stromal cell-derived factor-1beta; D008715:Methionine; D002118:Calcium