A Novel CCR5 Mutation Common in Sooty Mangabeys Reveals SIVsmm Infection of CCR5-Null Natural Hosts and Efficient Alternative Coreceptor Use In Vivo

Abstract

In contrast to HIV infection in humans and SIV in macaques, SIV infection of natural hosts including sooty mangabeys (SM) is non-pathogenic despite robust virus replication. We identified a novel SM CCR5 allele containing a two base pair deletion (Δ2) encoding a truncated molecule that is not expressed on the cell surface and does not support SIV entry in vitro. The allele was present at a 26% frequency in a large SM colony, along with 3% for a CCR5Δ24 deletion allele that also abrogates surface expression. Overall, 8% of animals were homozygous for defective CCR5 alleles and 41% were heterozygous. The mutant allele was also present in wild SM in West Africa. CD8+ and CD4+ T cells displayed a gradient of CCR5 expression across genotype groups, which was highly significant for CD8+ cells. Remarkably, the prevalence of natural SIVsmm infection was not significantly different in animals lacking functional CCR5 compared to heterozygous and homozygous wild-type animals. Furthermore, animals lacking functional CCR5 had robust plasma viral loads, which were only modestly lower than wild-type animals. SIVsmm primary isolates infected both homozygous mutant and wild-type PBMC in a CCR5-independent manner in vitro, and Envs from both CCR5-null and wild-type infected animals used CXCR6, GPR15 and GPR1 in addition to CCR5 in transfected cells. These data clearly indicate that SIVsmm relies on CCR5-independent entry pathways in SM that are homozygous for defective CCR5 alleles and, while the extent of alternative coreceptor use in SM with CCR5 wild type alleles is uncertain, strongly suggest that SIVsmm tropism and host cell targeting in vivo is defined by the distribution and use of alternative entry pathways in addition to CCR5. SIVsmm entry through alternative pathways in vivo raises the possibility of novel CCR5-negative target cells that may be more expendable than CCR5+ cells and enable the virus to replicate efficiently without causing disease in the face of extremely restricted CCR5 expression seen in SM and several other natural host species.

Dualtropic CXCR6/CCR5 Simian Immunodeficiency Virus (SIV) Infection of Sooty Mangabey Primary Lymphocytes: Distinct Coreceptor Use in Natural versus Pathogenic Hosts of SIV

“…SIV smm FFv2.1 and FFv5.1 Envs were cloned from a clade 1 SIV smm -infected sooty mangabey homozygous for the CCR5 wild-type gene (CCR5 wt/wt ) using single-genome amplification (SGA) as previously described (11)(12)(13). SIV smm FPm1.1 Env was SGA cloned from a CCR5 wt/wt clade 5 SIV smm -infected sooty mangabey (12).…”

“…The SIV smm E660 CP3C-P-A8 and SIV smm E660 CR54-PK-2A5 Envs were cloned by SGA from acutely SIVE660-infected rhesus macaques and were a gift from K. Barr and G. Shaw (University of Pennsylvania) (15,16). Env pseudotypes were generated using the HIV-1 pNL-Luc-E Ϫ R ϩ backbone as described previously (11,12,17). Briefly, 293T cells were cotransfected with pNLLuc-E Ϫ R ϩ and SIV Env plasmid using Fugene (Promega).…”

“…We recently identified a deletion allele of CCR5 in SM that results in abrogation of protein expression and is common among wild and captive SM (11). Approximately 8% of captive SM are homozygous for CCR5 deletion alleles and thus genetically deficient in CCR5.…”

Simian-Human Immunodeficiency Viruses and Their Impact on Non-Human Primate Models for AIDS

“…This immunologic attenuation collectively contributes to limited T-cell apoptosis and maintenance of peripheral CD4+ T-cells even though viral loads comparable to those in pathogenic SIV infection are observed [17][18][19]. The precise mechanism that triggers the downregulated immune response is unclear, but is likely to involve a combination of proposed processes that include, (1) enhanced responses of immunosuppressive regulatory T-cells and IL-17 producing Th17 cells (2) a robust early innate immune response that is swiftly constrained, and (3) controlled regulation of cellular factors or receptors associated with activation, apoptosis, or virus binding [20][21][22][23][24][25][26][27][28][29][30][31][32]. Furthermore, in contrast to the massive immune depletion that occurs in the gastrointestinal (GI) tract of non-natural hosts of SIV or HIV infection, natural NHP SIV hosts maintain GI epithelial integrity and exhibit a lack of microbial translocation that may in part account for minimal systemic immune activation [33,34].…”

Agonistic Strategies and Spatial Distribution in Captive Sooty Mangabeys (Cercocebus Atys)

“…Sooty mangabeys provide information of human interest in a variety of disciplines, including immunology (Riddick et al, 2010), epidemiology (Santiago et al, 2005) and paleoanthropology (Daegling et al, 2011). The genus Cercocebus, which includes mangabeys, belongs to the Cercopithecidae family known as the Old World monkeys.…”