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SAMHD1-dependent retroviral control and escape in mice
Jan Rehwinkel1, Jonathan Maelfait, Anne Bridgeman
11] Immunobiology Laboratory, Cancer Research UK, London Research Institute, London, UK [2] Medical Research Council Human Immunology Unit, Radcliffe Department of Medicine, Medical Research Council Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
Sterile alpha motif and histidine-aspartic domain-containing protein 1 (SAMHD1) restricts HIV-1 in cells. In vivo studies show SAMHD1 restricts lentiviruses by depleting deoxynucleoside triphosphates, confirming its antiviral role.
Area of Science:
- Virology
- Immunology
- Molecular Biology
Background:
- SAMHD1 acts as a host restriction factor against HIV-1 in cultured cells.
- SAMHD1 mutations are linked to autoimmune disorders and cancers.
- SAMHD1's in vivo antiviral activity remained unconfirmed.
Purpose of the Study:
- To investigate the in vivo antiviral activity of SAMHD1.
- To determine if SAMHD1 deficiency impacts autoimmune disease development in mice.
- To elucidate the mechanism of SAMHD1-mediated viral restriction in vivo.
Main Methods:
- Generation of Samhd1 null mice.
- Analysis of autoimmune phenotypes in Samhd1(-/-) mice.
- Assessment of HIV-1 vector infection in Samhd1(-/-) cells and mice.
- Evaluation of deoxynucleoside triphosphate (dNTP) levels and reverse transcriptase (RT) affinity.
Main Results:
- Samhd1 null mice did not develop autoimmune disease but showed a type I interferon signature.
- SAMHD1 deficiency led to elevated dNTP levels but did not increase HIV-1 vector infection in mice.
- HIV-1 vectors with lower dNTP affinity RT were restricted by SAMHD1 in vivo, indicating nucleotide starvation is key.
- SAMHD1 restricts lentiviruses in vivo through nucleotide starvation.
Conclusions:
- SAMHD1 possesses in vivo antiviral activity against lentiviruses.
- Nucleotide starvation is an evolutionarily conserved antiviral mechanism mediated by SAMHD1.
- SAMHD1's role in viral restriction is confirmed in a whole-organism context.
