Differential utilization of CCR5 by macrophage and T cell tropic simian immunodeficiency virus strains

Differential utilization of CCR5 by macrophage and T cell tropic simian immunodeficiency virus strains

^*Department of Pathology and Laboratory Medicine and ^§Division of Hematology-Oncology, University of Pennsylvania, Philadelphia, PA 19104; ^†Tulane University Primate Research Center, Covington, LA 70433; ^‡Division of Comparative Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21205; ^¶IRIBHN, Université Libre de Bruxelles, Campus Erasme, 808 route de Lennik, B-1070 Brussels, Belgium; ^‖James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202; and ^**Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814-4799

Abstract

Certain chemokine receptors serve as cofactors for HIV type 1 envelope (env)-mediated cell–cell fusion and virus infection of CD4-positive cells. Macrophage tropic (M-tropic) HIV-1 isolates use CCR5, and T cell tropic (T-tropic) strains use CXCR4. To investigate the cofactors used by simian immunodeficiency viruses (SIV), we tested four T-tropic and two M-tropic SIV env proteins for their ability to mediate cell–cell fusion with cells expressing CD4 and either human or nonhuman primate chemokine receptors. Unlike HIV-1, both M- and T-tropic SIV envs used CCR5 but not CXCR4 or the other chemokine receptors tested. However, by testing a panel of CCR5/CCR2b chimeras, we found that the structural requirements for CCR5 utilization by M-tropic and T-tropic SIV strains were different. T-tropic SIV strains required the second extracellular loop of CCR5 whereas a closely related M-tropic SIV strain could, like M-tropic HIV-1 strains, use the amino-terminal domain of CCR5. As few as two amino acid changes in the SIV env V3 domain affected the regions of CCR5 that were critical for fusogenic activity. Receptor signaling was not required for either fusion or infection. Our results suggest that viral tropism may be influenced not only by the coreceptors used by a given virus strain but also by how a given coreceptor is used.

Footnotes

↵ ‡‡ To whom reprint requests should be addressed. e-mail: doms{at}mail.med.upenn.edu.
Anthony S. Fauci, National Institute of Allergy and Infectious Diseases, Bethesda, MD
ABBREVIATIONS:

HIV-1,

HIV type 1;

envelope,

env;

M-tropic,

macrophage tropic;

T-tropic,

T cell tropic;

SIV,

simian immunodeficiency virus