title: Pathogenesis of simian immunodeficiency virus encephalitis: viral determinants of neurovirulence.
abstract: To examine the relationship between macrophage tropism and neurovirulence, macaques were inoculated with two recombinant hybrid viruses derived from the parent viruses SIVmac239, a lymphocyte-tropic, non-neurovirulent clone, and SIV/17E-Br, a macrophage-tropic, neurovirulent virus strain. The first recombinant, SIV/17E-Cl, contained the portion of the env gene that encodes the surface glycoprotein and a short segment of the transmembrane glycoprotein of SIV/17E-Br in the backbone of SIVmac239. Unlike SIVmac239, SIV/17E-Cl replicated productively in macrophages, demonstrating that sequences in the surface portion of env determine macrophage tropism. None of five macaques inoculated with SIV/17E-Cl developed simian immunodeficiency virus (SIV) encephalitis. The second recombinant, SIV/17E-Fr, which contained the entire env and nef genes and the 3' long terminal repeat of SIV/17E-Br in the SIVmac239 backbone, was also macrophage tropic. Six of nine macaques inoculated with SIV/17E-Fr developed SIV encephalitis ranging from mild to moderate in severity, indicating a significant (P = 0.031) difference in the neurovirulence of the two recombinants. In both groups of macaques, CD4+ cell counts declined gradually during infection and there was no significant difference in the rate of the decline between the two groups of macaques. This study demonstrated that macrophage tropism alone is not sufficient for the development of neurological disease. In addition, it showed that while sequences in the surface portion of the envelope gene determine macrophage tropism, additional sequences derived from the transmembrane portion of envelope and/or nef confer neurovirulence.
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Mankowski
authors.forename: M T
authors.initials: MT
authors.lastname: Flaherty
authors.forename: J P
authors.initials: JP
authors.lastname: Spelman
authors.forename: D A
authors.initials: DA
authors.lastname: Hauer
authors.forename: P J
authors.initials: PJ
authors.lastname: Didier
authors.forename: A M
authors.initials: AM
authors.lastname: Amedee
authors.forename: M
authors.initials: M
authors.lastname: Murphey-Corb
authors.forename: L M
authors.initials: LM
authors.lastname: Kirstein
authors.forename: A
authors.initials: A
authors.lastname: Muñoz
authors.forename: J E
authors.initials: JE
authors.lastname: Clements
authors.forename: M C
authors.initials: MC
authors.lastname: Zink
mesh_terms: D000818:Animals; D000956:Antigens, Viral / Q000097:blood; D018791:CD4 Lymphocyte Count; D004279:DNA, Viral / Q000032:analysis; D018792:Encephalitis, Viral / Q000209:etiology*; D015752:Genes, env; D008251:Macaca; D008264:Macrophages / Q000821:virology; D016133:Polymerase Chain Reaction; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000472:pathogenicity*; D014774:Virulence
chemical_list: D000956:Antigens, Viral; D004279:DNA, Viral