The Dynamic Interplay between HIV-1, SAMHD1, and the Innate Antiviral Response

Abstract

The innate immune response constitutes the first cellular line of defense against initial HIV-1 infection. Immune cells sense invading virus and trigger signaling cascades that induce antiviral defenses to control or eliminate infection. Professional antigen-presenting cells located in mucosal tissues, including dendritic cells and macrophages, are critical for recognizing HIV-1 at the site of initial exposure. These cells are less permissive to HIV-1 infection compared to activated CD4⁺ T-cells, which is mainly due to host restriction factors that serve an immediate role in controlling the establishment or spread of viral infection. However, HIV-1 can exploit innate immune cells and their cellular factors to avoid detection and clearance by the host immune system. Sterile alpha motif and HD-domain containing protein 1 (SAMHD1) is the mammalian deoxynucleoside triphosphate triphosphohydrolase responsible for regulating intracellular dNTP pools and restricting the replication of HIV-1 in non-dividing myeloid cells and quiescent CD4⁺ T-cells. Here, we review and analyze the latest literature on the antiviral function of SAMHD1, including the mechanism of HIV-1 restriction and the ability of SAMHD1 to regulate the innate immune response to viral infection. We also provide an overview of the dynamic interplay between HIV-1, SAMHD1, and the cell-intrinsic antiviral response to elucidate how SAMHD1 modulates HIV-1 infection in non-dividing immune cells. A more complete understanding of SAMHD1's role in the innate immune response to HIV-1 infection may help develop stratagems to enhance its antiviral effects and to more efficiently block HIV-1 replication and avoid the pathogenic result of viral infection.

Keywords: HIV-1; infection; innate immunity; myeloid cells; sterile alpha motif and HD-domain containing protein 1.

Figure 1

Innate immune sensing of HIV-1 DNA. HIV-1 undergoes uncoating through the interaction between viral capsid and host factors (31, 32). Reverse transcribed HIV-1 DNA, mainly abortive transcripts, activates cytosolic DNA sensors IFI16 and cyclic GMP-AMP synthase (cGAS) resulting in TANK-binding kinase 1 (TBK1)-mediated phosphorylation and nuclear translocation of hetero-or-homo dimers of interferon regulatory factor-3 (IRF3) and IRF7 and induction of type-I IFN response. Expression of ISGs allows for immune activation and the induction of an antiviral state of the cell. gRNA, HIV-1 genomic RNA; cDNA, complementary DNA; vRNA, viral RNA; dsDNA, double-stranded DNA; STING, stimulator of IFN genes; the letter P indicates phosphorylation.

Figure 2

SAMHD1 negatively regulates the innate immune sensing of HIV-1 DNA. SAMHD1 blocks HIV-1 infection through intracellular dNTP depletion, thus preventing the accumulation of viral DNA accessible to sensing by IFI16 and cyclic GMP-AMP synthase (cGAS) and the activation of the type-I interferon (IFN-I) response. The dNTPase activity of SAMHD1 is structurally regulated. Consecutive binding of dGTP/GTP and any dNTP to two allosteric sites provokes formation of the catalytically active tetramer, which can be destabilized by phosphorylation, oxidation, or the binding of single-stranded nucleic acids (ssNAs). dN, deoxynucleosides; PPPs, triphosphate; two linked letters S indicate the disulfide bond.