The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1998/12/2057/ $5.00
The Journal of Experimental Medicine, Volume 188, Number 11, December 7, 1998 2057-2065

Articles

Natural Infection of a Homozygous {Delta}24 CCR5 Red-capped Mangabey with an R2b-Tropic Simian Immunodeficiency Virus

Zhiwei Chen*, Douglas Kwon*, Zhanqun Jin*, Simon Monard*, Paul Telfer*,{ddagger}, Morris S. Jones*,§, Chang Y. Lu||, Roberto F. Aguilar, David D. Ho*, and Preston A. Marx*,**

From the * Aaron Diamond AIDS Research Center, The Rockefeller University, New York 10016; the {ddagger} Department of Anthropology and the § Department of Microbiology, New York University Medical Center, New York 10016; || Centre International de Recherches Medicales, Franceville, Gabon; the Audubon Park Zoo, New Orleans, Louisiana 70118; and the ** Department of Tropical Medicine and Tulane Regional Primate Research Center, Tulane University Medical Center, Covington, Louisiana 70433

A homozygous 24-bp deletion ({Delta}24) was found in the CC chemokine receptor 5 (CCR5) of 11 out of 15 red-capped mangabeys (RCMs), Cercocebus torquatus torquatus, both in Africa and in an American zoo. The CCR5 {Delta}24 defect encompassed eight amino acids in frame in the fourth transmembrane region. Unexpectedly, RCM-009, one of 11 homozygotes ({Delta}24CCR5/ {Delta}24CCR5), was found to be naturally infected with a divergent simian immunodeficiency virus (SIV) strain, which was not R5-tropic, but used CCR2b (R2b) as its major coreceptor. SIVrcmGab1 was the only R2b-tropic SIV among other divergent SIVs tested. Cells transfected with the {Delta}24 CCR5 did not support entry of R5-tropic SIVmac, SIVcpz, SIVmne, HIV-2, or HIV-1, and were also inactive in signal transduction mediated by β-chemokines. At 86.6%, the {Delta}24 allelic frequency was significantly higher than that of the 32-bp deletion found in humans. The {Delta}24 frequency was 4.1% in 34 sooty mangabeys (SMs), a geographically isolated subspecies that was naturally infected with R5-tropic SIV. Finding identical deletions in two mangabey subspecies separated for 10,000 years or more dates the {Delta}24 CCR5 deletion as ancient. However, the source of the selective pressure for the high rate of CCR5 deletion in RCMs remains to be determined. The high allelic frequency of the {Delta}24 CCR5 in RCMs, in comparison to that of SMs, suggests that R2b-tropism may have been acquired by SIVrcm, as an adaptation to CCR5 genetic defects appeared in its host.

Key Words: SIVrcm • CCR5 • CCR2b • mangabey • {Delta}24 defect

Address correspondence to Preston A. Marx, Tulane Regional Primate Research Center, 18703 Three Rivers Rd., Covington, LA 70433. Phone: 504-892-2040; Fax: 504-893-1352; E-mail: pmarx{at}adarc.org

Abbreviations used: AGM/agm, African green monkey; CPZ/ cpz, chimpanzee; GFP, green fluorescent protein; MIP, macrophage inflammatory protein; RCM/rcm, red-capped mangabey; SIV, simian immunodeficiency virus; SM/sm, sooty mangabey.


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