title: Divergent Simian Arteriviruses Cause Simian Hemorrhagic Fever of Differing Severities in Macaques.
abstract: Simian hemorrhagic fever (SHF) is a highly lethal disease in captive macaques. Three distinct arteriviruses are known etiological agents of past SHF epizootics, but only one, simian hemorrhagic fever virus (SHFV), has been isolated in cell culture. The natural reservoir(s) of the three viruses have yet to be identified, but African nonhuman primates are suspected. Eleven additional divergent simian arteriviruses have been detected recently in diverse and apparently healthy African cercopithecid monkeys. Here, we report the successful isolation in MARC-145 cell culture of one of these viruses, Kibale red colobus virus 1 (KRCV-1), from serum of a naturally infected red colobus (Procolobus [Piliocolobus] rufomitratus tephrosceles) sampled in Kibale National Park, Uganda. Intramuscular (i.m.) injection of KRCV-1 into four cynomolgus macaques (Macaca fascicularis) resulted in a self-limiting nonlethal disease characterized by depressive behavioral changes, disturbance in coagulation parameters, and liver enzyme elevations. In contrast, i.m. injection of SHFV resulted in typical lethal SHF characterized by mild fever, lethargy, lymphoid depletion, lymphoid and hepatocellular necrosis, low platelet counts, increased liver enzyme concentrations, coagulation abnormalities, and increasing viral loads. As hypothesized based on the genetic and presumed antigenic distance between KRCV-1 and SHFV, all four macaques that had survived KRCV-1 injection died of SHF after subsequent SHFV injection, indicating a lack of protective heterotypic immunity. Our data indicate that SHF is a disease of macaques that in all likelihood can be caused by a number of distinct simian arteriviruses, although with different severity depending on the specific arterivirus involved. Consequently, we recommend that current screening procedures for SHFV in primate-holding facilities be modified to detect all known simian arteriviruses.
  
  
  
  Outbreaks of simian hemorrhagic fever (SHF) have devastated captive Asian macaque colonies in the past. SHF is caused by at least three viruses of the family Arteriviridae: simian hemorrhagic fever virus (SHFV), simian hemorrhagic encephalitis virus (SHEV), and Pebjah virus (PBJV). Nine additional distant relatives of these three viruses were recently discovered in apparently healthy African nonhuman primates. We hypothesized that all simian arteriviruses are potential causes of SHF. To test this hypothesis, we inoculated cynomolgus macaques with a highly divergent simian arterivirus (Kibale red colobus virus 1 [KRCV-1]) from a wild Ugandan red colobus. Despite being only distantly related to red colobuses, all of the macaques developed disease. In contrast to SHFV-infected animals, KRCV-1-infected animals survived after a mild disease presentation. Our study advances the understanding of an important primate disease. Furthermore, our data indicate a need to include the full diversity of simian arteriviruses in nonhuman primate SHF screening assays.
authors.affiliation: Integrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Fort Detrick, Frederick, Maryland, USA.
authors.forename: Victoria
authors.identifier: 0000-0002-6588-4308
authors.initials: V
authors.lastname: Wahl-Jensen
authors.affiliation: Integrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Fort Detrick, Frederick, Maryland, USA.
authors.forename: Joshua C
authors.identifier: 0000-0002-5677-3841
authors.initials: JC
authors.lastname: Johnson
authors.affiliation: University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Michael
authors.identifier: 0000-0003-2813-3705
authors.initials: M
authors.lastname: Lauck
authors.affiliation: University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Jason T
authors.identifier: 0000-0001-8076-2598
authors.initials: JT
authors.lastname: Weinfurter
authors.affiliation: University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Louise H
authors.initials: LH
authors.lastname: Moncla
authors.affiliation: University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Weiler
authors.affiliation: University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Olivia
authors.initials: O
authors.lastname: Charlier
authors.affiliation: Integrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Fort Detrick, Frederick, Maryland, USA.
authors.forename: Oscar
authors.initials: O
authors.lastname: Rojas
authors.affiliation: Integrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Fort Detrick, Frederick, Maryland, USA.
authors.forename: Russell
authors.initials: R
authors.lastname: Byrum
authors.affiliation: Integrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Fort Detrick, Frederick, Maryland, USA.
authors.forename: Dan R
authors.initials: DR
authors.lastname: Ragland
authors.affiliation: Integrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Fort Detrick, Frederick, Maryland, USA.
authors.forename: Louis
authors.identifier: 0000-0003-2913-489X
authors.initials: L
authors.lastname: Huzella
authors.affiliation: Integrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Fort Detrick, Frederick, Maryland, USA.
authors.forename: Erika
authors.identifier: 0000-0002-5835-1212
authors.initials: E
authors.lastname: Zommer
authors.affiliation: Integrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Fort Detrick, Frederick, Maryland, USA.
authors.forename: Melanie
authors.initials: M
authors.lastname: Cohen
authors.affiliation: Integrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Fort Detrick, Frederick, Maryland, USA.
authors.forename: John G
authors.identifier: 0000-0002-1529-8191
authors.initials: JG
authors.lastname: Bernbaum
authors.affiliation: Integrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Fort Detrick, Frederick, Maryland, USA.
authors.forename: Yíngyún
authors.identifier: 0000-0002-1101-0920
authors.initials: Y
authors.lastname: Caì
authors.affiliation: Integrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Fort Detrick, Frederick, Maryland, USA.
authors.forename: Hannah B
authors.initials: HB
authors.lastname: Sanford
authors.affiliation: Integrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Fort Detrick, Frederick, Maryland, USA.
authors.forename: Steven
authors.identifier: 0000-0002-9349-338X
authors.initials: S
authors.lastname: Mazur
authors.affiliation: Emerging Viral Pathogens Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Fort Detrick, Frederick, Maryland, USA.
authors.forename: Reed F
authors.identifier: 0000-0002-4312-0550
authors.initials: RF
authors.lastname: Johnson
authors.affiliation: Biostatistics Research Branch, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Qin
authors.affiliation: United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland, USA.
authors.forename: Gustavo F
authors.identifier: 0000-0001-5062-1938
authors.initials: GF
authors.lastname: Palacios
authors.affiliation: University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Adam L
authors.identifier: 0000-0002-6560-9680
authors.initials: AL
authors.lastname: Bailey
authors.affiliation: Integrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Fort Detrick, Frederick, Maryland, USA Emerging Viral Pathogens Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Fort Detrick, Frederick, Maryland, USA.
authors.forename: Peter B
authors.identifier: 0000-0002-9775-3724
authors.initials: PB
authors.lastname: Jahrling
authors.affiliation: University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Tony L
authors.identifier: 0000-0003-3962-4913
authors.initials: TL
authors.lastname: Goldberg
authors.affiliation: University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: David H
authors.identifier: 0000-0003-2139-470X
authors.initials: DH
authors.lastname: O'Connor
authors.affiliation: University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Thomas C
authors.identifier: 0000-0001-9831-6895
authors.initials: TC
authors.lastname: Friedrich
authors.affiliation: Integrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Fort Detrick, Frederick, Maryland, USA kuhnjens@mail.nih.gov.
authors.forename: Jens H
authors.identifier: 0000-0002-7800-6045
authors.initials: JH
authors.lastname: Kuhn
mesh_terms: D000818:Animals; D018018:Arterivirus / Q000235:genetics / Q000254:growth & development / Q000302:isolation & purification* / Q000472:pathogenicity*; D018174:Arterivirus Infections / Q000276:immunology / Q000503:physiopathology / Q000662:veterinary* / Q000821:virology; D002460:Cell Line; D003104:Colobus / Q000821:virology*; D006482:Hemorrhagic Fevers, Viral / Q000276:immunology / Q000503:physiopathology / Q000662:veterinary* / Q000821:virology; D008099:Liver / Q000737:chemistry / Q000201:enzymology; D008252:Macaca fascicularis / Q000821:virology*; D008297:Male; D008992:Monkey Diseases / Q000276:immunology / Q000503:physiopathology / Q000821:virology*; D014454:Uganda; D019562:Viral Load