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PLoS One. 2012;7(8):e42801. doi: 10.1371/journal.pone.0042801. Epub 2012 Aug 27.

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

Author information

1
Division of Infectious Diseases, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America. shruthiravimohan@gmail.com

Erratum in

  • PLoS One. 2013;8(3). doi: 10.1371/annotation/050af66e-a935-46e6-96ec-5ac7e0fc4dfc.

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.

PMID:
22952612
PMCID:
PMC3428313
DOI:
10.1371/journal.pone.0042801
[Indexed for MEDLINE]
Free PMC Article

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