title: Early emergence and selection of a SIV-LTR C/EBP site variant in SIV-infected macaques that increases virus infectivity.
abstract: CCAAT/enhancer binding protein (C/EBP)β, and C/EBP binding sites in the HIV/SIV-long terminal repeat (LTR) are crucial for regulating transcription and for IFNβ-mediated suppression of virus replication in macrophages, the predominant source of productive virus replication in the brain. We investigated sequence variation within the SIV-LTR C/EBP sites that may be under selective pressure in vivo and therefore associated with disease progression. Using the SIV-macaque model, we examined viral LTR sequences derived from the spleen, a site of macrophage and lymphocyte infection, and the brain from macaques euthanized at 10, 21, 42, 48 and 84 days postinoculation (p.i.). A dominant variant, DS1C/A, containing an adenine-to-guanine substitution and a linked cytosine-to-adenine substitution in the downstream (DS1) C/EBP site, was detected in the spleen at 10 days p.i. The DS1C/A genotype was not detected in the brain until 42 days p.i., after which it was the predominant replicating genotype in both brain and spleen. Functional characterization of the DS1C/A containing SIV showed increased infectivity with or without IFNβ treatment over the wild-type virus, SIV/17E-Fr. The DS1C/A C/EBP site had higher affinity for both protein isoforms of C/EBPβ compared to the wild-type DS1 C/EBP site. Cytokine expression in spleen compared to brain implicated IFNβ and IL-6 responses as part of the selective pressures contributing to emergence of the DS1C/A genotype in vivo. These studies demonstrate selective replication of virus containing the DS1C/A genotype that either emerges very early in spleen and spreads to the brain, or evolves independently in the brain when IFNβ and IL-6 levels are similar to that found in spleen earlier in infection.
authors.affiliation: Division of Infectious Diseases, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America. shruthiravimohan@gmail.com
authors.forename: Shruthi
authors.initials: S
authors.lastname: Ravimohan
authors.forename: Lucio
authors.initials: L
authors.lastname: Gama
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Engle
authors.forename: M Christine
authors.initials: MC
authors.lastname: Zink
authors.forename: Janice E
authors.initials: JE
authors.lastname: Clements
mesh_terms: D000818:Animals; D001921:Brain / Q000821:virology; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics*; D018450:Disease Progression; D014644:Genetic Variation; D005838:Genotype; D057809:HEK293 Cells; D006801:Humans; D017403:In Situ Hybridization; D016899:Interferon-beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008251:Macaca; D008264:Macrophages / Q000166:cytology; D016097:Simian Acquired Immunodeficiency Syndrome / Q000821:virology*; D015302:Simian Immunodeficiency Virus / Q000235:genetics*; D013154:Spleen / Q000821:virology; D020079:Terminal Repeat Sequences / Q000235:genetics*; D013997:Time Factors; D014779:Virus Replication
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D015850:Interleukin-6; D016899:Interferon-beta