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Journal of Virology, June 1999, p. 4582-4589, Vol. 73, No. 6
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

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

Otto O. Yang,1 Stephen L. Swanberg,2 Zhijian Lu,2 Michelle Dziejman,1 John McCoy,2 Andrew D. Luster,1 Bruce D. Walker,1 and Steven H. Herrmann2,*

AIDS Research Center and Infectious Disease Unit, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129,1 and Infectious Disease and Molecular Biology-Gene Expression, Genetics Institute Inc., Cambridge, Massachusetts 021402

Received 2 November 1998/Accepted 22 February 1999

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.

* Corresponding author. Mailing address: Infectious Disease Research, Wyeth-Cambridge, Genetics Institute, 87 Cambridge Park Dr., Cambridge, MA 02140. Phone: (617) 498-8245. Fax: (617) 498-8878. E-mail: sherrmann{at}genetics.com.

Journal of Virology, June 1999, p. 4582-4589, Vol. 73, No. 6
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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