title: Barriers to Infection of Human Cells by Feline Leukemia Virus: Insights into Resistance to Zoonosis.
abstract: The human genome displays a rich fossil record of past gammaretrovirus infections, yet no current epidemic is evident, despite environmental exposure to viruses that infect human cellsin vitroFeline leukemia viruses (FeLVs) rank high on this list, but neither domestic nor workplace exposure has been associated with detectable serological responses. Nonspecific inactivation of gammaretroviruses by serum factors appears insufficient to explain these observations. To investigate further, we explored the susceptibilities of primary and established human cell lines to FeLV-B, the most likely zoonotic variant. Fully permissive infection was common in cancer-derived cell lines but was also a feature of nontransformed keratinocytes and lung fibroblasts. Cells of hematopoietic origin were generally less permissive and formed discrete groups on the basis of high or low intracellular protein expression and virion release. Potent repression was observed in primary human blood mononuclear cells and a subset of leukemia cell lines. However, the early steps of reverse transcription and integration appear to be unimpaired in nonpermissive cells. FeLV-B was subject to G→A hypermutation with a predominant APOBEC3G signature in partially permissive cells but was not mutated in permissive cells or in nonpermissive cells that block secondary viral spread. Distinct cellular barriers that protect primary human blood cells are likely to be important in protection against zoonotic infection with FeLV.IMPORTANCEDomestic exposure to gammaretroviruses such as feline leukemia viruses (FeLVs) occurs worldwide, but the basis of human resistance to infection remains incompletely understood. The potential threat is evident from the human genome sequence, which reveals many past epidemics of gammaretrovirus infection, and from recent cross-species jumps of gammaretroviruses from rodents to primates and marsupials. This study examined resistance to infection at the cellular level with the most prevalent human cell-tropic FeLV variant, FeLV-B. We found that blood cells are uniquely resistant to infection with FeLV-B due to the activity of cellular enzymes that mutate the viral genome. A second block, which appears to suppress viral gene expression after the viral genome has integrated into the host cell genome, was identified. Since cells derived from other normal human cell types are fully supportive of FeLV replication, innate resistance of blood cells could be critical in protecting against cross-species infection.
authors.affiliation: MRC University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Anne
authors.initials: A
authors.lastname: Terry
authors.affiliation: MRC University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Anna
authors.initials: A
authors.lastname: Kilbey
authors.affiliation: MRC University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Asif
authors.initials: A
authors.lastname: Naseer
authors.affiliation: Tulane University, New Orleans, Louisiana, USA.
authors.forename: Laura S
authors.initials: LS
authors.lastname: Levy
authors.affiliation: Tulane University, New Orleans, Louisiana, USA.
authors.forename: Shamim
authors.initials: S
authors.lastname: Ahmad
authors.affiliation: MRC University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Ciorsdaidh
authors.initials: C
authors.lastname: Watts
authors.affiliation: MRC University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Nancy
authors.initials: N
authors.lastname: Mackay
authors.affiliation: School of Veterinary Medicine, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Ewan
authors.initials: E
authors.lastname: Cameron
authors.affiliation: MRC University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Sam
authors.initials: S
authors.lastname: Wilson
authors.affiliation: MRC University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, United Kingdom James.Neil@glasgow.ac.uk.
authors.forename: James C
authors.initials: JC
authors.lastname: Neil
mesh_terms: D000071480:APOBEC-3G Deaminase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002415:Cats; D045744:Cell Line, Tumor; D004198:Disease Susceptibility; D015870:Gene Expression; D016679:Genome, Viral; D057809:HEK293 Cells; D006801:Humans; D005256:Leukemia Virus, Feline / Q000502:physiology*; D009154:Mutation; D012192:Retroviridae Infections / Q000821:virology*; D013045:Species Specificity; D056189:Viral Tropism; D016662:Virus Integration; D014779:Virus Replication; D015047:Zoonoses / Q000821:virology
chemical_list: D000071480:APOBEC-3G Deaminase; C464924:APOBEC3G protein, human
keywords: APOBEC; feline leukemia virus; restriction factors; zoonosis