title: 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.
authors.affiliation: Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Nadeene E
authors.initials: NE
authors.lastname: Riddick
authors.forename: Emilia A
authors.initials: EA
authors.lastname: Hermann
authors.forename: Lamorris M
authors.initials: LM
authors.lastname: Loftin
authors.forename: Sarah T
authors.initials: ST
authors.lastname: Elliott
authors.forename: Winston C
authors.initials: WC
authors.lastname: Wey
authors.forename: Barbara
authors.initials: B
authors.lastname: Cervasi
authors.forename: Jessica
authors.initials: J
authors.lastname: Taaffe
authors.forename: Jessica C
authors.initials: JC
authors.lastname: Engram
authors.forename: Bing
authors.initials: B
authors.lastname: Li
authors.forename: James G
authors.initials: JG
authors.lastname: Else
authors.forename: Yingying
authors.initials: Y
authors.lastname: Li
authors.forename: Beatrice H
authors.initials: BH
authors.lastname: Hahn
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Derdeyn
authors.forename: Donald L
authors.initials: DL
authors.lastname: Sodora
authors.forename: Cristian
authors.initials: C
authors.lastname: Apetrei
authors.forename: Mirko
authors.initials: M
authors.lastname: Paiardini
authors.forename: Guido
authors.initials: G
authors.lastname: Silvestri
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Collman
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002460:Cell Line; D002469:Cell Separation; D016665:Cercocebus atys / Q000235:genetics*; D005434:Flow Cytometry; D005838:Genotype; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D016133:Polymerase Chain Reaction; D019713:Receptors, CCR5 / Q000096:biosynthesis / Q000235:genetics*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000235:genetics*; D015302:Simian Immunodeficiency Virus / Q000235:genetics*; D014162:Transfection; D019562:Viral Load / Q000235:genetics
chemical_list: D019713:Receptors, CCR5