Natural Infection of a Homozygous Δ24 CCR5 Red-capped Mangabey with an R2b-Tropic Simian Immunodeficiency Virus

Abstract

A homozygous 24-bp deletion (Δ24) 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 Δ24 defect encompassed eight amino acids in frame in the fourth transmembrane region. Unexpectedly, RCM-009, one of 11 homozygotes (Δ24CCR5/ Δ24CCR5), 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 Δ24 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 Δ24 allelic frequency was significantly higher than that of the 32-bp deletion found in humans. The Δ24 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 Δ24 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 Δ24 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.

Use of Inhibitors To Evaluate Coreceptor Usage by Simian and Simian/Human Immunodeficiency Viruses and Human Immunodeficiency Virus Type 2 in Primary Cells

“…SIV rcm replicated efficiently in wild-type and ⌬32-CCR5 PBMC (Tables 4 and 5), consistent with its lack of dependence on CCR5 for entry into PBMC (15). SIV mac 239 and SIV mac 251 also replicated efficiently in CEMx174 cells, as found previously (18), but SIV rcm replication was inefficient in these cells (Table 4).…”

“…Any possible use of CCR2 that might be masked by TAK-779 is not supported by the complete inhibition of the same isolates by AOP-RANTES. This chemokine derivative does not block viral entry via CCR2, at least for SIV rcm , which is the only truly CCR2-tropic virus yet identified (15). Another advantage of TAK-779 is that it avoids the potential complications of AOP-RANTES-induced enhancement of attachment and entry of X4 HIV-1 isolates (44,108).…”

“…SIV rcm clearly uses CCR2 as its primary coreceptor (15), in a manner that we have shown is sensitive to TAK-779. The ability of SIV rcm to enter GHOST-CD4 cells expressing US28 and V28 in vitro is likely to be of limited relevance to the replication of this virus in red-capped mangabeys.…”

A binding pocket for a small molecule inhibitor of HIV-1 entry within the transmembrane helices of CCR5

“…Zhang and J.P.M., unpublished data). TAK-779 interacts with CCR2 (24), the major coreceptor for SIV rcm (33).…”

“…However, there is significant conservation of the TM domain residues involved in the TAK-779 binding pocket among the chemokine receptor family. Of the residues at which an alanine substitution conferred strong TAK-779 resistance, Tyr 37 , Trp 86 , and Tyr 108 are conserved in all CC-chemokine receptors (except in CCR8 where residue 86 is Gln); a conservative substitution of Val for Leu 33 or Ser for Thr 123 also occurs in some receptors. Positions in CCR5 where a mutation resulted in moderate resistance to TAK-779 are more variable.…”