Early emergence and selection of a SIV-LTR C/EBP site variant in SIV-Infected macaques that increases virus infectivity

Shruthi Ravimohan, Lucio Gama, Elizabeth L. Engle, Mary Christine Zink, Janice E Clements

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere42801
JournalPLoS One
Volume7
Issue number8
DOIs
StatePublished - Aug 27 2012

Fingerprint

CCAAT-Enhancer-Binding Proteins
terminal repeat sequences
Terminal Repeat Sequences
Macaca
Viruses
binding proteins
Brain
pathogenicity
Binding Sites
spleen
Spleen
brain
viruses
Virus Replication
virus replication
Genotype
genotype
Macrophages
Adenine
adenine

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Early emergence and selection of a SIV-LTR C/EBP site variant in SIV-Infected macaques that increases virus infectivity. / Ravimohan, Shruthi; Gama, Lucio; Engle, Elizabeth L.; Zink, Mary Christine; Clements, Janice E.

In: PLoS One, Vol. 7, No. 8, e42801, 27.08.2012.

Research output: Contribution to journalArticle

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