SAMHD1 … and Viral Ways around It

Abstract

The SAM and HD domain-containing protein 1 (SAMHD1) is a dNTP triphosphohydrolase that plays a crucial role for a variety of different cellular functions. Besides balancing intracellular dNTP concentrations, facilitating DNA damage repair, and dampening excessive immune responses, SAMHD1 has been shown to act as a major restriction factor against various virus species. In addition to its well-described activity against retroviruses such as HIV-1, SAMHD1 has been identified to reduce the infectivity of different DNA viruses such as the herpesviruses CMV and EBV, the poxvirus VACV, or the hepadnavirus HBV. While some viruses are efficiently restricted by SAMHD1, others have developed evasion mechanisms that antagonize the antiviral activity of SAMHD1. Within this review, we summarize the different cellular functions of SAMHD1 and highlight the countermeasures viruses have evolved to neutralize the restriction factor SAMHD1.

Keywords: HIV; SAMHD1; Vpx; dNTP hydrolase; herpesviruses; restriction factor; viral antagonism; viral interference; viral kinases.

Figure 1

Cellular functions of SAMHD1. The dNTP triphosphohydrolase SAMHD1 is an important regulator of dNTP levels. A correct balance of the cellular dNTP pool has been shown to be important for cell-cycle control and genome integrity. SAMHD1 is a mediator of double-strand break (DSB) repair and ensures the progression of DNA replication. Mutations in the SAMHD1 gene have been identified in various types of cancer. Furthermore, SAMHD1 potently restricts viral infectivity of retroviruses and DNA viruses, and blocks the activity of endogenous retroelements. Mutations in SAMHD1 are correlated with autoimmune diseases such as Aicardi–Goutières syndrome, resulting in elevated type I IFN levels. SAMHD1 also impairs the innate immune sensing of viral infections by interfering with cGAS/STING nucleic acid recognition and NFκB/IRF signaling pathways.

Figure 2

Viral countermeasures to circumvent the intrinsic restriction factor SAMHD1. Retroviruses without a Vpx-like function, such as HIV-1, encode a highly efficient reverse transcriptase (“Super” RT) that enables the virus to reverse-transcribe its genome despite the presence of active SAMHD1 and the resulting low dNTP level. HIV-2 and related SIVs encode the small accessory protein Vpx (or Vpr with a Vpx-like function), which ties SAMHD1 to a Cullin E3 ubiquitin ligase complex, resulting in ubiquitination and subsequent proteasomal degradation of SAMHD1. Herpesviruses, especially β- and γ-herpesviruses, rely on their conserved serine/threonine protein kinases to phosphorylate and thereby inactivate SAMHD1. In addition, HCMV infection also induces the proteasomal degradation of SAMHD1. Infection with other viruses, such as HSV-2, HBV, and HPV16, has been reported to cause a reduction in SAMHD1 RNA or protein levels, suggesting that additional unknown mechanisms exist to circumvent the SAMHD1-mediated restriction. Ub: ubiquitination, P: phosphorylation.