title: Characterization of simian immunodeficiency virus (SIV) that induces SIV encephalitis in rhesus macaques with high frequency: role of TRIM5 and major histocompatibility complex genotypes and early entry to the brain.
abstract: Although nonhuman primate models of neuro-AIDS have made tremendous contributions to our understanding of disease progression in the central nervous system (CNS) of human immunodeficiency virus type 1 (HIV-1)-infected individuals, each model holds advantages and limitations. In this study, in vivo passage of SIVsmE543 was conducted to obtain a viral isolate that can induce neuropathology in rhesus macaques. After a series of four in vivo passages in rhesus macaques, we have successfully isolated SIVsm804E. SIVsm804E shows efficient replication in peripheral blood mononuclear cells (PBMCs) and monocyte-derived macrophages (MDMs) in vitro and induces neuro-AIDS in high frequencies in vivo. Analysis of the acute phase of infection revealed that SIVsm804E establishes infection in the CNS during the early phase of the infection, which was not observed in the animals infected with the parental SIVsmE543-3. Comprehensive analysis of disease progression in the animals used in the study suggested that host major histocompatibility complex class I (MHC-I) and TRIM5α genotypes influence the disease progression in the CNS. Taken together, our findings show that we have successfully isolated a new strain of simian immunodeficiency virus (SIV) that is capable of establishing infection in the CNS at early stage of infection and causes neuropathology in infected rhesus macaques at a high frequency (83%) using a single inoculum, when animals with restrictive MHC-I or TRIM5α genotypes are excluded. SIVsm804E has the potential to augment some of the limitations of existing nonhuman primate neuro-AIDS models.
  
  
  OBJECTIVE
  Human immunodeficiency virus (HIV) is associated with a high frequency of neurologic complications due to infection of the central nervous system (CNS). Although the use of antiviral treatment has reduced the incidence of severe complications, milder disease of the CNS continues to be a significant problem. Animal models to study development of neurologic disease are needed. This article describes the development of a novel virus isolate that induces neurologic disease in a high proportion of rhesus macaques infected without the need for prior immunomodulation as is required for some other models.
authors.affiliation: Laboratory of Molecular Microbiology, NIAID, NIH, Bethesda, Maryland, USA.
authors.forename: Kenta
authors.initials: K
authors.lastname: Matsuda
authors.affiliation: Division of AIDS, NIAID, NIH, Bethesda, Maryland, USA.
authors.forename: Que
authors.initials: Q
authors.lastname: Dang
authors.affiliation: MedImmune, LLC, Gaithersburg, Maryland, USA.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Brown
authors.affiliation: AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Brandon F
authors.initials: BF
authors.lastname: Keele
authors.affiliation: Laboratory of Molecular Microbiology, NIAID, NIH, Bethesda, Maryland, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Wu
authors.affiliation: Laboratory of Molecular Microbiology, NIAID, NIH, Bethesda, Maryland, USA.
authors.forename: Ilnour
authors.initials: I
authors.lastname: Ourmanov
authors.affiliation: Laboratory of Molecular Microbiology, NIAID, NIH, Bethesda, Maryland, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Goeken
authors.affiliation: Laboratory of Molecular Microbiology, NIAID, NIH, Bethesda, Maryland, USA.
authors.forename: Sonya
authors.initials: S
authors.lastname: Whitted
authors.affiliation: Laboratory of Molecular Microbiology, NIAID, NIH, Bethesda, Maryland, USA.
authors.forename: Nadeene E
authors.initials: NE
authors.lastname: Riddick
authors.affiliation: Laboratory of Molecular Microbiology, NIAID, NIH, Bethesda, Maryland, USA.
authors.forename: Alicia
authors.initials: A
authors.lastname: Buckler-White
authors.affiliation: Laboratory of Molecular Microbiology, NIAID, NIH, Bethesda, Maryland, USA vhirsch@niaid.nih.gov.
authors.forename: Vanessa M
authors.initials: VM
authors.lastname: Hirsch
mesh_terms: D000818:Animals; D001921:Brain / Q000821:virology; D018792:Encephalitis, Viral / Q000235:genetics / Q000276:immunology*; D005838:Genotype; D017958:Lentiviruses, Primate; D008253:Macaca mulatta; D008285:Major Histocompatibility Complex / Q000235:genetics / Q000276:immunology*; D008969:Molecular Sequence Data; D011506:Proteins / Q000235:genetics / Q000276:immunology*; D017422:Sequence Analysis, DNA; D016097:Simian Acquired Immunodeficiency Syndrome / Q000150:complications / Q000276:immunology*; D015302:Simian Immunodeficiency Virus / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases; D014774:Virulence
chemical_list: D011506:Proteins; C482587:TRIM5(alpha) protein, rhesus monkey; D044767:Ubiquitin-Protein Ligases