The Central Nervous System as a Reservoir for Simian Immunodeficiency Virus (SIV): Steady‐State Levels of SIV DNA in Brain from Acute through Asymptomatic Infection

Clements, Janice E.; Babas, Tahar; Mankowski, Joseph L.; Suryanarayana, K.; Piatak, Michael; Tarwater, Patrick M.; Lifson, Jeffrey D.; Zink, M. Christine

doi:10.1086/343768

Cited by 158 publications

(173 citation statements)

References 30 publications

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“…We have previously demonstrated that acute SIV replication is suppressed in the brain without the decrease in viral DNA levels, supporting the conclusion that transcriptional suppression occurs in the brain (3,4). The innate immune response to virus infection, particularly IFN␤ and the induction of LIP mediated by CUGBP1, is crucial for suppression of SIV transcription (4,47), thereby providing a mechanism for HIV/SIV latency in macrophages in the central nervous system.…”

supporting

confidence: 70%

“…Once Tat is expressed, it binds to the TAR element, assisted by C/EBP␤ bound to the DS1 site and thus contributes, in part, to the surge of SIV RNA production and virus replication during acute infection (peaking at 10 days p.i.) in the brain (3,69). Virus replication in macrophages in the brain triggers the innate immune responses and production of IFN␤ (8,69), which activates CUGBP-1 required for IFN␤-induced translation of the dominant-negative LIP isoform (47).…”

Section: Discussionmentioning

confidence: 99%

“…and peaks by 10 days p.i. (3). Between 14 and 21 days p.i., SIV RNA expression in the brain is down-regulated, at least in part, at a transcriptional level because SIV DNA levels remain constant during this time (3,4).…”

Section: And Simian Immunodeficiency Virus (Siv)-infected Cellsmentioning

confidence: 99%

“…(3). Between 14 and 21 days p.i., SIV RNA expression in the brain is down-regulated, at least in part, at a transcriptional level because SIV DNA levels remain constant during this time (3,4). Previous reports in our model have implicated IFN␤ in the suppression of acute SIV replication in the brain (4,5).…”

Section: And Simian Immunodeficiency Virus (Siv)-infected Cellsmentioning

confidence: 99%

“…The higher binding affinity of LIP for the JC1 and DS1 sites compared with C/EBP␤ (1.6-and 3.0-fold, respectively) provides a mechanistic link between IFN␤-mediated suppression of SIV transcription in macrophages and the establishment of SIV latency in brain (3)(4)(5)47). We postulate that having two functional C/EBP sites that mediate transcriptional suppression (as compared with one for basal transcription) accelerates the transition from active to suppressed transcription.…”

mentioning

confidence: 99%

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Regulation of SIVmac239 Basal Long Terminal Repeat Activity and Viral Replication in Macrophages

Ravimohan

Gama

Barber

et al. 2010

Journal of Biological Chemistry

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CCAAT/enhancer-binding protein (C/EBP) ␤ and C/EBP sites in the HIV-1 long terminal repeat (LTR) are crucial for HIV-1 replication in monocyte/macrophages and for the ability of interferon ␤ (IFN␤) to inhibit ongoing active HIV replication in these cells. This IFN␤-mediated down-regulation involves induction of the truncated, dominant-negative isoform of C/EBP␤ referred to as liver-enriched transcriptional inhibitory protein (LIP). Although binding of the C/EBP␤ isoform to C/EBP sites in the simian immunodeficiency virus (SIV) LTR has previously been examined, the importance of these sites in core promoter-mediated transcription, virus replication, IFN␤-mediated regulation, and the relative binding of the two isoforms (C/EBP␤ and LIP) has not been investigated. Here, we specifically examine two C/EBP sites, JC1 (؊100 bp) and DS1 (؉134 bp), located within the minimal region of the SIV LTR, required for core promoter-mediated transcription and virus replication in macrophages. Our studies revealed that the JC1 but not DS1 C/EBP site is important for basal level transcription, whereas the DS1 C/EBP site is imperative for productive virus replication in primary macrophages. In contrast, either JC1 or DS1 C/EBP site is sufficient to mediate IFN␤-induced down-regulation of SIV LTR activity and virus replication in these cells. We also characterized the differential binding properties of C/EBP␤ and LIP to the JC1 and DS1 sites. In conjunction with previous studies from our laboratory, we demonstrate the importance of these sites in virus gene expression, and we propose a model for their role in establishing latency and persistence in macrophages in the brain.

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supporting

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Section: And Simian Immunodeficiency Virus (Siv)-infected Cellsmentioning

confidence: 99%

Section: And Simian Immunodeficiency Virus (Siv)-infected Cellsmentioning

confidence: 99%

mentioning

confidence: 99%

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Regulation of SIVmac239 Basal Long Terminal Repeat Activity and Viral Replication in Macrophages

Ravimohan

Gama

Barber

et al. 2010

Journal of Biological Chemistry

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Neuroprotective and Anti–Human Immunodeficiency Virus Activity of Minocycline

Zink

Uhrlaub

DeWitt

et al. 2005

JAMA

207

173

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Altered cutaneous nerve regeneration in a simian immunodeficiency virus / macaque intracutaneous axotomy model

Ebenezer

Laast

Dearman

et al. 2009

J of Comparative Neurology

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To characterize the regenerative pattern of cutaneous nerves in SIV-infected and uninfected macaques, excisional axotomies were performed in non-glabrous skin at 14-day intervals. Samples were examined after immunostaining for the pan-axonal marker PGP 9.5 and the Schwann cell marker p75 nerve growth factor receptor. Collateral sprouting of axons from adjacent uninjured superficial dermal nerve bundles was the initial response to axotomy. Both horizontal collateral sprouts and dense vertical regeneration of axons from the deeper dermis led to complete, rapid reinnervation of the epidermis at the axotomy site. In contrast to the slower, incomplete reinnervation previously noted in humans after this technique, in both SIV-infected and uninfected macaques, epidermal reinnervation was rapid and completed by 56 days post-axotomy. p75 was densely expressed on the Schwann cells of uninjured nerve bundles along the excision line and on epidermal Schwann cell processes. In both SIV-infected and uninfected macaques, Schwann cell process density was highest at the earliest time points post-axotomy and then declined at a similar rate. However, SIV-infection delayed epidermal nerve fiber regeneration and remodeling of new sprouts at every time point post-axotomy, and SIV-infected animals consistently had lower mean epidermal Schwann cell densities suggesting that Schwann cell guidance and support of epidermal nerve fiber regeneration may account for altered nerve regeneration. The relatively rapid regeneration time and the completeness of epidermal reinnervation in this macaque model provides a useful platform for assessing the efficacy of neurotrophic or regenerative drugs for sensory neuropathies including those caused by HIV, diabetes mellitus, medications, and toxins.

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The Central Nervous System as a Reservoir for Simian Immunodeficiency Virus (SIV): Steady‐State Levels of SIV DNA in Brain from Acute through Asymptomatic Infection

Cited by 158 publications

References 30 publications

Regulation of SIVmac239 Basal Long Terminal Repeat Activity and Viral Replication in Macrophages

Regulation of SIVmac239 Basal Long Terminal Repeat Activity and Viral Replication in Macrophages

Neuroprotective and Anti–Human Immunodeficiency Virus Activity of Minocycline

Altered cutaneous nerve regeneration in a simian immunodeficiency virus / macaque intracutaneous axotomy model

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