Early emergence and selection of a SIV-LTR C/EBP site variant in SIV-infected macaques that increases virus infectivity.
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 investiga...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2012-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3428313?pdf=render |
| _version_ | 1818976099852353536 |
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| author | Shruthi Ravimohan Lucio Gama Elizabeth L Engle M Christine Zink Janice E Clements |
| author_facet | Shruthi Ravimohan Lucio Gama Elizabeth L Engle M Christine Zink Janice E Clements |
| author_sort | Shruthi Ravimohan |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-20T16:06:28Z |
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| id | doaj.art-dfb7efad5d5c48fb9b494b03f303c8ba |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-20T16:06:28Z |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-dfb7efad5d5c48fb9b494b03f303c8ba2022-12-21T19:34:09ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0178e4280110.1371/journal.pone.0042801Early emergence and selection of a SIV-LTR C/EBP site variant in SIV-infected macaques that increases virus infectivity.Shruthi RavimohanLucio GamaElizabeth L EngleM Christine ZinkJanice E ClementsCCAAT/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.http://europepmc.org/articles/PMC3428313?pdf=render |
| spellingShingle | Shruthi Ravimohan Lucio Gama Elizabeth L Engle M Christine Zink Janice E Clements Early emergence and selection of a SIV-LTR C/EBP site variant in SIV-infected macaques that increases virus infectivity. PLoS ONE |
| title | Early emergence and selection of a SIV-LTR C/EBP site variant in SIV-infected macaques that increases virus infectivity. |
| title_full | Early emergence and selection of a SIV-LTR C/EBP site variant in SIV-infected macaques that increases virus infectivity. |
| title_fullStr | Early emergence and selection of a SIV-LTR C/EBP site variant in SIV-infected macaques that increases virus infectivity. |
| title_full_unstemmed | Early emergence and selection of a SIV-LTR C/EBP site variant in SIV-infected macaques that increases virus infectivity. |
| title_short | Early emergence and selection of a SIV-LTR C/EBP site variant in SIV-infected macaques that increases virus infectivity. |
| title_sort | early emergence and selection of a siv ltr c ebp site variant in siv infected macaques that increases virus infectivity |
| url | http://europepmc.org/articles/PMC3428313?pdf=render |
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