Selective CXCR4 antagonism by Tat: Implications for in vivo expansion of coreceptor use by HIV-1

Selective CXCR4 antagonism by Tat: Implications for in vivo expansion of coreceptor use by HIV-1

Laboratories of ^†Molecular Microbiology and ^‡Host Defenses, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892-0460

Communicated by Robert C. Gallo, Institute of Human Virology, Baltimore, MD (received for review January 3, 2000)

Abstract

Chemokines and chemokine receptors play important roles in HIV-1 infection and tropism. CCR5 is the major macrophage-tropic coreceptor for HIV-1 whereas CXC chemokine receptor 4 (CXCR4) serves the counterpart function for T cell-tropic viruses. An outstanding biological mystery is why only R5-HIV-1 is initially detected in new seroconvertors who are exposed to R5 and X4 viruses. Indeed, X4 virus emerges in a minority of patients and only in the late stage of disease, suggesting that early negative selection against HIV-1–CXCR4 interaction may exist. Here, we report that the HIV-1 Tat protein, which is secreted from virus-infected cells, is a CXCR4-specific antagonist. Soluble Tat selectively inhibited the entry and replication of X4, but not R5, virus in peripheral blood mononuclear cells (PBMCs). We propose that one functional consequence of secreted Tat is to select against X4 viruses, thereby influencing the early in vivo course of HIV-1 disease.

Footnotes

↵ * H.X., C.N., and H.L.T. contributed equally to this work.
↵ § Deceased July 10, 1998.
↵ ¶ To whom reprint requests should be addressed at: Building 4, Room 306, 9000 Rockville Pike, National Institutes of Health, Bethesda, MD 20892-0460. E-mail: kj7e{at}nih.gov.
Abbreviations:

RANTES,

regulated upon activation, normal T cell expressed and secreted;

SDF,

stromal cell-derived factor;

CCR5,

CC chemokine receptor 5;

CXCR4,

CXC chemokine receptor 4;

PBMC,

peripheral blood mononuclear cell;

MIP,

macrophage inflammatory protein;

LTR,

long terminal repeat;

RT,

reverse transcriptase;

PVDF,

poly(vinylidene difluoride);

MBP,

maltose-binding protein;

GST,

glutathione S-transferase;

MAGI,

multinuclear activation of a galactosidase indicator