Trends in Microbiology
Volume 23, Issue 11, November 2015, Pages 680-692
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Review
SAMHD1: At the Crossroads of Cell Proliferation, Immune Responses, and Virus Restriction

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SAMHD1 is a host restriction factor that limits retroviral replication at the reverse transcription step, and it is counteracted by HIV-2 Vpx, which targets SAMHD1 for degradation by the proteasome.

The mechanism of SAMHD1 virus restriction is controversial; both dNTPase and RNase functions have been proposed as essential for its antiviral activity. However, the exonuclease activity cannot be associated with the SAMHD1 active site.

SAMHD1 restriction is deactivated by phosphorylation mediated by cyclin-dependent kinases and is tightly linked to cell-cycle entry and progression.

Recent studies have established an association between SAMHD1 restriction, innate sensing of DNA, and protective immune responses.

SAMHD1 links virus replication, innate immune responses, and cell-cycle progression, determining disease outcomes of viral infections, autoimmune diseases, and cancer.

SAMHD1 is a triphosphohydrolase enzyme that controls the intracellular level of deoxyribonucleoside triphosphates (dNTPs) and plays a role in innate immune sensing and autoimmune disease. SAMHD1 has also been identified as an intrinsic virus restriction factor, inactivated through degradation by HIV-2 Vpx or through a post-transcriptional regulatory mechanism. Phosphorylation of SAMHD1 by cyclin-dependent kinases has been strongly associated with inactivation of the virus restriction mechanism, providing an association between virus replication and cell proliferation. Tight regulation of cell proliferation suggests that viruses, particularly HIV-1 replication, latency, and reactivation, may be similarly controlled by multiple checkpoint mechanisms that, in turn, regulate dNTP levels. In this review, we discuss how SAMHD1 is a viral restriction factor, the mechanism associated with viral restriction, the pathway leading to its inactivation in proliferating cells, and how strategies aimed at controlling virus restriction could lead to a functional cure for HIV.

Section snippets

Identification of SAMHD1 as an HIV Restriction Factor in Non-Cycling Cells

SAMHD1 (sterile alpha motif and histidine-aspartate-domain-containing protein 1) is a member of a unique group of host restriction factors that limit retroviral replication at distinct stages of the viral life cycle (Box 1). Human immunodeficiency virus type 1 (HIV-1) is relatively inefficient in infecting nondividing cells, such as monocytes, dendritic cells (DCs), and quiescent CD4+ T cells. Infection of these cells can be enhanced by the HIV-2 accessory protein Vpx, based on the observed

Structure–Function of SAMHD1

Given the known nucleic-acid-metabolizing functions of proteins associated with AGS [15] and the presence of an HD motif proposed to have phosphohydrolase activities [16], the capacity of SAMHD1 to hydrolyze distinct nucleic acid forms has been assessed 17, 18, 19. SAMHD1 also contains a nucleic-acid-binding domain shown to overlap with the HD domain [20].

The first crystal structure of the catalytic core of SAMHD1 revealed activity against dNTPs. SAMHD1 has triphosphohydrolase activity that

The Retroviral Restriction Function of SAMHD1: dNTPase or RNase?

First evidence of the retroviral restriction function of SAMHD1 showed that SAMHD1 overexpression in U937 cells caused a drop in the intracellular dNTP pool [18]. This observation, together with the fact that both the complete protein and the isolated HD domain show triphosphohydrolase activity, provide a plausible hypothesis for SAMHD1-mediated viral restriction: depletion of the intracellular dNTP pool limits the availability of dNTPs for viral reverse transcription (Figure 1B) 17, 37.

The Molecular Pathway Leading to SAMHD1 Inactivation

SAMHD1 does not restrict HIV-1 replication in cycling cells [44], indicating a close relationship between SAMHD1 activity and a state of reduced metabolic activity. Indeed, resting T cells or undifferentiated monocytes have low dNTP levels because of reduced ribonucleotide reductase (RNR2) activity (the enzyme responsible for dNTP synthesis 35, 45) and the control of the dNTP pool by active SAMHD1.

Immune cell activation is commonly initiated after antigen and/or cytokine stimulation as a

The Role of SAMHD1 in HIV-1 Disease

Despite the clear evidence of host restriction factors in cell culture and their mechanism of action in vitro, the role of viral restriction in disease is not evident. The lack of clear genetic evidence supporting a role for antiviral restriction markers in disease suggests a secondary or insufficient effect in virus control in vivo. Nevertheless, several studies indicate that SAMHD1 may indeed play a role in HIV pathogenesis and disease. For example, SAMHD1 knockout mice have shown that SAMHD1

SAMHD1 Viral Restriction, More Than Retroviruses

In addition to the well-documented effect of SAMHD1 in HIV-1 infection, its catalytic activity strongly suggests that the depletion of dNTP levels could affect the replication of any virus requiring DNA polymerase function for replication but lacking a countermeasure such as HIV-2 Vpx. SAMHD1 has been reported to restrict a wide array of divergent retroviruses [61], including feline immunodeficiency virus (FIV), simian immunodeficiency virus (SIV), and equine infectious anemia virus (EIAV).

The Role of SAMHD1 in Other Diseases beyond Virus Control

It is now clear that defects in nucleotide metabolism are involved in multiple diseases, including cancer, immunological disorders, mitochondrial syndromes, kidney and liver pathologies, aging, and viral and bacterial infections. Some of these conditions caused by imbalanced rNTP/dNTP pools are uncommon, belong to complex groups of genetically and clinically heterogeneous diseases, and lack a definite genetic diagnosis, characteristics that make these disorders extremely difficult to manage,

SAMHD1: Friend or Foe?

Unlike HIV-1, HIV-2 and multiple SIV strains have evolved the capacity to degrade SAMHD1 71, 72. Therefore, compared to HIV-1, HIV-2 is able to replicate better in resting T cells or DCs and macrophages. As HIV-1 is not able to counteract SAMHD1-mediated restriction, it might be erroneously hypothesized that HIV-1 infection would be attenuated compared to HIV-2. This conundrum has raised doubts about SAMHD1 restriction being either beneficial or detrimental to the host.

A hallmark of HIV disease

Strategies for an HIV-1 Infection Cure

SAMHD1 represents a unique element linking virus replication, the innate immune response, and cell-cycle progression that, in turn, strongly signal the course and outcome of disease, not only for HIV-1 infection but also for other viral infections, autoimmune diseases, and cancer. Our understanding of SAMHD1 function is important for identifying alternative mechanisms to combat multiple diseases. Inappropriate or chronic detection of self nucleic acids by the innate immune system underlies many

Play It [Again] SAMHD12

In summary, we provide a general overview of the discovery and current state of knowledge of a rather peculiar restriction factor (Figure 4, Key Figure). Many issues regarding SAMHD1 restriction remain unanswered (see Outstanding Questions). It remains to be resolved whether SAMHD1 restriction of retroviruses and DNA viruses is a purely antiviral mechanism of cell defense and an intrinsic part of the innate immune system. These assumptions are supported by SAMHD1's apparent causal role in

Acknowledgments

Work in our laboratory has been funded in part by the Spanish MINECO and FIS projects BFU2012-31569, PI13/01083, and CP14/00016 and by the RETICS AIDS Research Network. Ester Ballana is a Miguel Servet fellow from FIS.

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