miRNAs and SAMHD1 regulation in vitro and in a model of HIV CNS disease
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Pilakka-Kanthikeel et al. recently reported higher levels of the retroviral restriction factor sterile alpha motif and histidine/aspartic acid domain-containing protein 1 (SAMHD1) in astrocytes than in microglia, suggesting that SAMHD1 levels might explain in part the relatively refractory nature of astrocytes to retroviral replication. These findings are consistent with our studies of simian and human immunodeficiency virus infection of astrocytes and macrophages. Similarly, a role for two host microRNAs in post-transcriptional regulation of SAMHD1 agrees with our in vitro results and those of others. However, data from an animal model of HIV neurologic disorders may not be consistent with robust miRNA-mediated regulation of SAMHD1 in vivo.
KeywordsHuman Immunodeficiency Virus Human Immunodeficiency Virus Infection Eradication Therapy Uninfected Control Refractory Nature
- 3′ UTR
3′ untranslated region
central nervous system
human immunodeficiency virus
SAM-domain and HD-domain containing protein 1
Letter to the editor
We were pleased to read the recent article of Pilakka-Kanthikeel and colleagues, reporting higher levels of the retroviral restriction factor sterile alpha motif and histidine/aspartic acid domain-containing protein 1 (SAMHD1) in astrocytes than in microglia . The data suggest that SAMHD1 levels might explain in part the relatively refractory nature of astrocytes to retroviral replication. These findings are consistent with our studies of simian and human immunodeficiency virus (SIV and HIV) infection of astrocytes and macrophages (, "Regulation of the SAMHD1 transcript during retroviral infection of the central nervous system," submitted); see also the different results on SAMHD1 in elite suppressor populations [3-5]. Similarly, a role for two host microRNAs (miRNAs) in post-transcriptional regulation of SAMHD1 agrees with our results  and Swaminathan et al. .
Seeking to determine whether there is a tissue-level, in vivo correlation between SAMHD1 and miRNAs found to regulate the transcript in vitro, we measured SAMHD1 and miRNA expression in a well-characterized simian model of HIV disease , including uninfected controls. In the model, thalamic SAMHD1 expression increased significantly after infection (p < 0.03), while miR-181a was significantly downregulated (p < 0.001). This regulation in opposite directions could be interpreted as consistent with a miR-181a-SAMHD1 interaction. However, further analysis revealed no correlation of miR-181a and SAMHD1 in any of the following groups: acute phase infection (Fig. 1b), progression to disease (Fig. 1c), or all samples, including uninfected controls (Fig. 1d). There was also no correlation of SAMHD1 with levels of miR-155 or miR-34a, which in fact tended to increase during infection (data not shown). These results recall a previous finding in which the RNA binding protein ZFP36 (tristetraprolin) could be suppressed by miRNAs in vitro but showed little evidence of negative correlation with the same miRNAs in vivo .
While our findings temper our initial enthusiasm about miRNA-mediated control of SAMHD1, we are not prepared to dismiss it entirely. Although the astrocyte is the most abundant cell type in the brain and appears to support higher levels of SAMHD1 expression than, e.g., macrophages ["Regulation of the SAMHD1 transcript during retroviral infection of the central nervous system," submitted] and microglia , the tissue-level profiling we performed may mask changes of miRNA or SAMHD1 expression in specific cells types or even the absence of certain miRNAs in disease-related cells . Similarly, focusing on single miRNA-to-target interactions ignores the regulatory “whole picture,” since a given miRNA-to-target interaction is governed not only by the abundance of each partner but also by the abundance of other partners . Finally, assuming adequate delivery methods, therapeutic antisense manipulation of anti-SAMHD1 miRNAs (for example, to help prevent cell-to-cell transmission during eradication therapy) could be performed at high concentrations not dissimilar to the in vitro manipulations that we and the authors performed. There may will be more to learn about miRNAs and SAMHD1 in the CNS.
This work was supported in part by NIH grant R21 AI102659 (KWW), NIMH pilot grant P30 MH075673 (to KWW), and by the National Center for Research Resources and the Office of Research Infrastructure Programs (ORIP) and the National Institutes of Health through grant number P40 OD013117.
- 1.Pilakka-Kanthikeel S, Raymond A, Atluri VS, Sagar V, Saxena SK, Diaz P, et al. Sterile alpha motif and histidine/aspartic acid domain-containing protein 1 (SAMHD1)-facilitated HIV restriction in astrocytes is regulated by miRNA-181a. J Neuroinflammation. 2015;12(1):66.PubMedCentralCrossRefPubMedGoogle Scholar
- 2.Buchanan EL, Espinoza DA, Sisk JM, Moyer A, Clements JE, Witwer KW. Expression and regulation of host restriction factor SAMHD1 during lentiviral infection of astrocytes and macrophages. In: Conference on Retroviruses and Opportunistic Infections. Atlanta, GA, USA; CROI, LLC, Alexandria, 2013Google Scholar
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