Credit: GETTY

Unlike infection of CD4+ T cells by HIV-1, infection of dendritic cells and macrophages is inefficient owing to the presence of the recently identified myeloid-specific restriction factor SAMHD1. This factor can be counteracted by viruses encoding Vpx, such as HIV-2 and sooty mangabey simian immunodeficiency virus (SIVSM); however, its mechanism of action was unclear. Writing in Nature Immunology, Lahouassa et al. now show that SAMHD1 functions by reducing intracellular levels of deoxynucleoside 5′-triphosphates (dNTPs) to below those required for the synthesis of viral DNA.

pharmacological intervention to alter intracellular dNTP levels could prove to be a viable therapeutic approach

SAMHD1 contains a central HD domain with putative nucleotidase and phosphodiesterase activities and, interestingly, has weak homology to an Enterococcus faecalis nucleotide-metabolizing enzyme. To investigate whether SAMHD1 has a role in regulating intracellular dNTP pools, Lahouassa et al. used short hairpin RNA to knock down the expression of SAMHD1 in phorbol 12-myristate 13-acetate (PMA)-treated THP1 human monocytic cells (a model system used in the place of macrophages). They found that cells lacking SAMHD1 had a larger dNTP pool than control cells. Similarly, addition of virus-like particles (VLPs) containing Vpx, which stimulates degradation of SAMHD1, to PMA-treated THP1 cells resulted in increased dNTP levels.

Further analysis showed that recombinant purified SAMHD1 could hydrolyse dGTP in vitro but was not active against the other three dNTPs (unless dGTP was also present, in which case SAMHD1 could hydrolyse all four dNTPs). Furthermore, expression of SAMHD1 in U937 cells, a monocytoid cell line that does not express endogenous SAMHD1, resulted in a >95% reduction in dNTP levels compared with levels in wild-type U937 cells. The authors also observed that incubating purified primary macrophages with deoxynucleosides to increase their pool of dNTPs or treating them with Vpx-containing VLPs enhanced the ability of HIV-1 to infect the cells.

Taken together, these data suggest that SAMHD1 is a dNTP phosphohydrolase that is necessary and sufficient for maintaining the low dNTP levels that are needed in macrophages to restrict HIV-1 replication. Furthermore, they indicate that pharmacological intervention to alter intracellular dNTP levels could prove to be a viable therapeutic approach for treating HIV-1 infection.