Effects of human SAMHD1 polymorphisms on HIV-1 susceptibility

Abstract

SAMHD1 is a human restriction factor that prevents efficient infection of macrophages, dendritic cells and resting CD4+ T cells by HIV-1. Here we explored the antiviral activity and biochemical properties of human SAMHD1 polymorphisms. Our studies focused on human SAMHD1 polymorphisms that were previously identified as evolving under positive selection for rapid amino acid replacement during primate speciation. The different human SAMHD1 polymorphisms were tested for their ability to block HIV-1, HIV-2 and equine infectious anemia virus (EIAV). All studied SAMHD1 variants block HIV-1, HIV-2 and EIAV infection when compared to wild type. We found that these variants did not lose their ability to oligomerize or to bind RNA. Furthermore, all tested variants were susceptible to degradation by Vpx, and localized to the nuclear compartment. We tested the ability of human SAMHD1 polymorphisms to decrease the dNTP cellular levels. In agreement, none of the different SAMHD1 variants lost their ability to reduce cellular levels of dNTPs. Finally, we found that none of the tested human SAMHD1 polymorphisms affected the ability of the protein to block LINE-1 retrotransposition.

Restricting retrotransposons: a review

“…Seven of eight AGS-related mutations in SAMHD1 reduced inhibition of cell culture LINE-1 retrotransposition by 40 % or more [ 168 ]. On the other hand, nine naturally occurring polymorphisms failed to alter SAMHD1 inhibition of retrotransposition [ 169 ]. One might expect patients with mutant SAMHD1 alleles to show increased retrotransposition; however, sequencing of bulk tissue and single neurons from the brain of one AGS patient revealed no increase of L1 insertions compared with controls [ 170 ].…”

Modulation of LINE-1 retrotransposition by a human SAMHD1 polymorphism

“…Interestingly, the nucleotides that codify S33 exhibit at least two described single nucleotide polymorphisms, in Korean individuals, that changes S33 to tyrosine or alanine (White et al, 2014). To understand the role of S33 in the ability of SAMHD1 to negatively modulate retrotransposition of the long interspersed element 1 (LINE-1) (Zhao et al, 2013), we used a reporter assay to measure LINE-1 retrotransposition in human HEK293T cells (Goodier et al, 2013).…”

“…Five days post-transfection, the occurrence of retrotransposition was determined by expression of EGFP measured by flow cytometry. As control, we have cotransfected the empty vector LPCX in HEK 293T cells as described (White et al, 2014). The defective LINE-1 construct, JM111, was used for determining the background levels of EGFP.…”

“…In addition, SAMHD1 has the ability to block LINE-1 retrotransposition (Hu et al, 2015; White et al, 2014; Zhao et al, 2013). Although several human SAMHD1 polymorphisms have been studied (Coon et al, 2012; White et al, 2014), none of the analyzed human SAMHD1 polymorphism have shown to exhibit a defect on the known functions of SAMHD1.…”

“…Most alleles of SAMHD1 encode a serine at this position (S33)(White et al, 2014), which is a residue that is permanently phosphorylated in the SAMHD1 protein (Pauls et al, 2014; Welbourn et al, 2013; White et al, 2013b). Here we explored the role of S33 in the ability of SAMHD1 to modulate the retrotransposition of the long interspersed element 1 (LINE-1).…”