The application of "molecular machines" in infectiology

SAMHD1 inhibits HIV replication in dormant CD4 cells

The sterile alpha motif (SAM) and histidine-aspartate domain-containing protein 1 (SAMHD1) is a triphosphohydrolase that catalyzes the hydrolysis of deoxyribonucleoside triphosphate into deoxyribonucleoside and triphosphate. Ian A. Taylor, from the Francis Crick Institute in London, reported on new insights about the structure and mechanism of the enzyme at the 25th CROI in Boston on March 6, 2018.

The functional importance of SAMHD1 was first recognized in 2009 due to its role in the development of Aicardi-Goutières Syndrome (AGS), indicated Ian Taylor. This is a very rare autosomal recessive hereditary disease, first described as progressive encephalopathy in 1984. In most children, the disease begins within the first 3 to 6 months of life with sudden movement, screaming attacks, sleep disorders or seizures. Arms and legs show increasing stiffness or spasticity, while the trunk may become limp and the children cannot hold their head or upper body properly upright. The disease typically relapses with phases of stabilization. Up to the age of 17, about 30% of those affected die. The symptoms are similar to chronic congenital viral infection but without the virus.

In 2011, the importance of SAMHD1 as a cellular restriction factor that inhibits HIV-1 replication in myeloid and dormant CD4 cells was demonstrated.

The structure of SAMHD1

SAMHD1 is a polypeptide with 626 amino acids. The central HD domain is associated with phosphohydrolase activity, while the C-terminal region interacts with Vpx/DCAF1 acting as deoxynucleoside triphosphate triphosphohydrolase. It splits triphosphate off the deoxynucleoside. This enzymatic effect is said to be the most important mechanism in inhibiting HIV replication. SAMHD1 thus reduces the pool of deoxynucleosides in the cell so that reverse transcription is no longer possible. In other words, the transcription of viral RNA into DNA is blocked.

The active form of SAMHD1 is a tetrameric protein containing four regulatory allosteric sites and four active sites for hydrolysis. The enzymatic activity is activated by deoxyguanosine triphosphate (dGTP), which binds to the allosteric sites. Enzyme activity is also regulated by tetramerization and T592 phosphorylation.

Taylor reported in detail on the clarification of the action mechanism of SAMHD1, plus with the current knowledge it is now possible to predict more precisely whether known or new antiviral or cytostatic substances are hydrolyzed by SAMHD1.

Taylor IA. Structure and mechanism of the SAMHD1 HIV-1 Restriction Factor. 25th CROI, Boston, March 6, 2018, Abstract 100.

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