How Samhd1 changes our view of viral restriction

Abstract

Recent studies have uncovered sterile alpha motif and HD domain 1 (SAMHD1) as the restriction factor that blocks HIV-1 replication in myeloid cells. In contrast to previously identified HIV-1 restriction factors, SAMHD1 does not meet a countermeasure developed by HIV-1. However, HIV-2 and certain simian immunodeficiency virus (SIV) strains express the auxiliary protein Vpx that potently blocks SAMHD1. It is therefore perplexing why this function has been lost or not acquired during the course of lentiviral evolution. This article summarizes the similarities and differences between SAMHD1 and other HIV-1 restriction factors, while highlighting the new questions that are emerging about the crosstalk between restriction factors and innate immune responses. Intrinsic cellular defenses and the viral arsenalHIV was identified as a human pathogen 28 years ago [1]. As a result of the inability of the human host to mount a coordinated immune response to the virus, infection by HIV usually results in chronic activation of the immune system that paradoxically allows for poorly controlled viral replication and immune exhaustion: the hallmark of AIDS. HIV-1 has evolved from SIVcpz, which causes AIDS in its natural chimpanzee host, whereas HIV-2 has evolved from SIVsm, which replicates to high levels in its natural simian host without causing disease [2] (Box 1). Hence, it is possible to speculate that lentiviruses and their host immune systems undergo an evolutionary co-adaptation to establish an equilibrium that will permit efficient spread without killing the host. However, tolerance to the infection is a multifactorial process that requires a fertile ground in the host as much as specific features of the virus. Here, we review the recent advances related to how host restriction factors may influence immune sensing and response against HIV. In particular, we examine the recent identification that the immune modulator SAMHD1 is the HIV restriction factor operating in myeloid cells, which are key players in the immune response during viral infection. A not so fertile ground?Upon entry into the human host, viruses are confronted with numerous blocks that oppose their replication (Figure 1). The first line of defense to be triggered is the so-called 'intrinsic' immune system. The intrinsic immune system includes proteins that detect the presence of the assailant pattern recognition receptors (PRRs), [Box 2] and which initiate a subsequent immune response, as well as proteins referred to as restriction factors that are directly devoted to arresting the replication cycle of the virus. To date, four restriction factors have been identified that specifically block HIV-1 replication: tripartite motif (TRIM)5α, apolipoprotein B mRNA-editing, enzyme-catalytic, polypeptide-like 3G Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts (APOBEC3G) (A3G), bone marrow stromal cell antigen 2 (BST-2) (also known as tetherin) and SAMHD1 [3][4][5][6][7]. Host restriction factor characteristicsTRIM5α interacts with...

Heterozygous colon cancer-associated mutations of SAMHD1 have functional significance

“…Germ-line mutations in SAMHD1 have been associated with Aicardi-Goutieres syndrome, a congenital autoimmune disease (23), and more recently SAMHD1 was shown to be an HIV-1 restriction factor operating in nondividing blood cells (24,25). Initially, the restriction function of SAMHD1 was attributed to its dNTPase activity, which was presumed to decrease the intracellular dNTP concentrations to levels incompatible with viral replication (26). Later, it was suggested that restriction of HIV-1 was primarily caused by the nuclease activity of SAMHD1 degrading viral RNA (27).…”

SAMHD1 is mutated recurrently in chronic lymphocytic leukemia and is involved in response to DNA damage

“…15,16 It is expressed widely across most tissue types including in the hemopoietic system and normal B cells. 17,18 In the case of HIV, SAMHD1 is responsible for maintaining the cellular dNTP pool at a level that is inadequate for replication of HIV-1 and other viruses, [19][20][21] thereby preventing viral propagation.…”

SAMHD1 Restricts Herpes Simplex Virus 1 in Macrophages by Limiting DNA Replication

“…The SAMHD1 enzyme restricts retrovirus infection in macrophages, dendritic cells, and resting CD4 ϩ T cells (28)(29)(30). It was identified through biochemical purification of the accessory factor Vpx encoded by certain lentiviruses (8,9).…”