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SAMHD1-dependent retroviral control and escape in mice

(2013) EMBO JOURNAL. 32(18). p.2454-2462
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Abstract
SAMHD1 is a host restriction factor for human immunodeficiency virus 1 (HIV-1) in cultured human cells. SAMHD1 mutations cause autoimmune Aicardi-Goutieres syndrome and are found in cancers including chronic lymphocytic leukaemia. SAMHD1 is a triphosphohydrolase that depletes the cellular pool of deoxynucleoside triphosphates, thereby preventing reverse transcription of retroviral genomes. However, in vivo evidence for SAMHD1's antiviral activity has been lacking. We generated Samhd1 null mice that do not develop autoimmune disease despite displaying a type I interferon signature in spleen, macrophages and fibroblasts. Samhd1(-/-) cells have elevated deoxynucleoside triphosphate (dNTP) levels but, surprisingly, SAMHD1 deficiency did not lead to increased infection with VSV-G-pseudotyped HIV-1 vectors. The lack of restriction is likely attributable to the fact that dNTP concentrations in SAMHD1-sufficient mouse cells are higher than the KM of HIV-1 reverse transcriptase (RT). Consistent with this notion, an HIV-1 vector mutant bearing an RT with lower affinity for dNTPs was sensitive to SAMHD1-dependent restriction in cultured cells and in mice. This shows that SAMHD1 can restrict lentiviruses in vivo and that nucleotide starvation is an evolutionarily conserved antiviral mechanism.
Keywords
Aicardi-Goutieres syndrome, HIV-1, SAMHD1, type I interferon, AICARDI-GOUTIERES-SYNDROME, RESTRICTION FACTOR SAMHD1, IMMUNODEFICIENCY-VIRUS TYPE-1, CHRONIC LYMPHOCYTIC-LEUKEMIA, INNATE IMMUNE-RESPONSE, CD4(+) T-CELLS, REVERSE-TRANSCRIPTASE, HIV-1 RESTRICTION, DENDRITIC CELLS, AUTOIMMUNE-DISEASE

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Chicago
Rehwinkel, Jan, Jonathan Maelfait, Anne Bridgeman, Rachel Rigby, Bruce Hayward, Rachel A Liberatore, Paul D Bieniasz, et al. 2013. “SAMHD1-dependent Retroviral Control and Escape in Mice.” Embo Journal 32 (18): 2454–2462.
APA
Rehwinkel, J., Maelfait, J., Bridgeman, A., Rigby, R., Hayward, B., Liberatore, R. A., Bieniasz, P. D., et al. (2013). SAMHD1-dependent retroviral control and escape in mice. EMBO JOURNAL, 32(18), 2454–2462.
Vancouver
1.
Rehwinkel J, Maelfait J, Bridgeman A, Rigby R, Hayward B, Liberatore RA, et al. SAMHD1-dependent retroviral control and escape in mice. EMBO JOURNAL. 2013;32(18):2454–62.
MLA
Rehwinkel, Jan et al. “SAMHD1-dependent Retroviral Control and Escape in Mice.” EMBO JOURNAL 32.18 (2013): 2454–2462. Print.
@article{8591846,
  abstract     = {SAMHD1 is a host restriction factor for human immunodeficiency virus 1 (HIV-1) in cultured human cells. SAMHD1 mutations cause autoimmune Aicardi-Goutieres syndrome and are found in cancers including chronic lymphocytic leukaemia. SAMHD1 is a triphosphohydrolase that depletes the cellular pool of deoxynucleoside triphosphates, thereby preventing reverse transcription of retroviral genomes. However, in vivo evidence for SAMHD1's antiviral activity has been lacking. We generated Samhd1 null mice that do not develop autoimmune disease despite displaying a type I interferon signature in spleen, macrophages and fibroblasts. Samhd1(-/-) cells have elevated deoxynucleoside triphosphate (dNTP) levels but, surprisingly, SAMHD1 deficiency did not lead to increased infection with VSV-G-pseudotyped HIV-1 vectors. The lack of restriction is likely attributable to the fact that dNTP concentrations in SAMHD1-sufficient mouse cells are higher than the KM of HIV-1 reverse transcriptase (RT). Consistent with this notion, an HIV-1 vector mutant bearing an RT with lower affinity for dNTPs was sensitive to SAMHD1-dependent restriction in cultured cells and in mice. This shows that SAMHD1 can restrict lentiviruses in vivo and that nucleotide starvation is an evolutionarily conserved antiviral mechanism.},
  author       = {Rehwinkel, Jan and Maelfait, Jonathan and Bridgeman, Anne and Rigby, Rachel and Hayward, Bruce and Liberatore, Rachel A and Bieniasz, Paul D and Towers, Greg J and Moita, Luis F and Crow, Yanick J and Bonthron, David T and Reis e Sousa, Caetano},
  issn         = {0261-4189},
  journal      = {EMBO JOURNAL},
  language     = {eng},
  number       = {18},
  pages        = {2454--2462},
  title        = {SAMHD1-dependent retroviral control and escape in mice},
  url          = {http://dx.doi.org/10.1038/emboj.2013.163},
  volume       = {32},
  year         = {2013},
}

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