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A novel CCR5 mutation common in sooty mangabeys reveals sivsmm infection of CCR5-null natural hosts and efficient alternative coreceptor use in vivo

Riddick, NE and Hermann, EA and Loftin, LM and Elliott, ST and Wey, WC and Cervasi, B and Taaffe, J and Engram, JC and Li, B and Else, JG and Li, Y and Hahn, BH and Derdeyn, CA and Sodora, DL and Apetrei, C and Paiardini, M and Silvestri, G and Collman, RG (2010) A novel CCR5 mutation common in sooty mangabeys reveals sivsmm infection of CCR5-null natural hosts and efficient alternative coreceptor use in vivo. PLoS Pathogens, 6 (8). 71 - 72. ISSN 1553-7366

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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 (D2) 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 CCR5D24 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. © 2010 Riddick et al.

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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Riddick, NE
Hermann, EA
Loftin, LM
Elliott, ST
Wey, WC
Cervasi, B
Taaffe, J
Engram, JC
Li, B
Else, JG
Li, Y
Hahn, BH
Derdeyn, CA
Sodora, DL
Apetrei, Capetreic@pitt.eduAPETREIC
Paiardini, M
Silvestri, G
Collman, RG
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorEmerman, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Centers: Other Centers, Institutes, Offices, or Units > Center for Vaccine Research
Date: 1 August 2010
Date Type: Publication
Journal or Publication Title: PLoS Pathogens
Volume: 6
Number: 8
Page Range: 71 - 72
DOI or Unique Handle: 10.1371/journal.ppat.1001064
Refereed: Yes
ISSN: 1553-7366
MeSH Headings: Amino Acid Sequence; Animals; Base Sequence; CD4-Positive T-Lymphocytes--metabolism; CD8-Positive T-Lymphocytes--metabolism; Cell Line; Cell Separation; Cercocebus atys--genetics; Flow Cytometry; Genotype; Humans; Molecular Sequence Data; Mutation; Polymerase Chain Reaction; Receptors, CCR5--biosynthesis; Receptors, CCR5--genetics; Simian Acquired Immunodeficiency Syndrome--genetics; Simian immunodeficiency virus--genetics; Transfection; Viral Load--genetics
Other ID: NLM PMC2928783
PubMed Central ID: PMC2928783
PubMed ID: 20865163
Date Deposited: 15 Aug 2012 17:55
Last Modified: 02 Feb 2019 16:56
URI: http://d-scholarship.pitt.edu/id/eprint/13397

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