Multifaceted activity of HIV Vpr/Vpx proteins: the current view of their virological functions

Fujita, Mikako; Otsuka, Masami; Nomaguchi, Masako; Adachi, Akio

doi:10.1002/rmv.636

Cited by 33 publications

(42 citation statements)

References 73 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is believed to have originated by gene duplication from Vpr [52]. Indeed, Vpr and Vpx proteins share several common features: (i) they are both specifically packaged into viral particles through an interaction with the p6 domain of the viral Gag precursor; and (ii) they both assemble an E3 ubiquitin ligase complex consisting of DCAF1 (previously known as Vpr-binding protein, VprBP), DDB1 (damage-specific DNA binding protein1), Cul4 (cullin4), and Rbx1 (Ring box protein1) [53,54]. The association of Vpr and Vpx with components of an E3 ubiquitin ligase complex indicted that these proteins, like Vif and Vpu, target cellular protein(s) for proteasomal degradation (Fig.…”

Section: Vpxmentioning

confidence: 99%

HIV accessory proteins versus host restriction factors

Strebel¹

2013

Current Opinion in Virology

112

View full text Add to dashboard Cite

Primate immunodeficiency viruses, including HIV-1, are characterized by the presence of accessory genes such as vif, vpr, vpx, vpu, and nef. Current knowledge indicates that none of the primate lentiviral accessory proteins has enzymatic activity. Instead, these proteins interact with cellular ligands to either act as adapter molecules to redirect the normal function of host factors for virus-specific purposes or to inhibit a normal host function by mediating degradation or causing intracellular mislocalization/sequestration of the factors involved. This review aims at providing an update of our current understanding of how Vif, Vpu, and Vpx control the cellular restriction factors APOBEC3G, BST-2, and SAMHD1, respectively.

show abstract

Section: Vpxmentioning

confidence: 99%

HIV accessory proteins versus host restriction factors

Strebel¹

2013

Current Opinion in Virology

112

View full text Add to dashboard Cite

show abstract

“…Whether vpx arose from gene duplication of vpr or through acquisition via recombination of viral strains remains debated and recent reviews detail their similarities and discrepancies [85,86]. Modeling of Vpx and Vpr from HIV-2 and HIV-1 origin reveals a highly similar 3D structure and high sequence homology.…”

Section: Boxmentioning

confidence: 99%

How Samhd1 changes our view of viral restriction

Laguette¹,

Benkirane²

2012

Trends in Immunology

View full text Add to dashboard Cite

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...

show abstract

“…HIV-2 and SIV from sooty mangabeys (SIVsm) but not HIV-1 encode the accessory protein Vpx [5] that provides a replication advantage in human myeloid cells [6], [7]. Moreover, Vpx deficient HIV-2/SIVsm viruses are attenuated in vivo [8].…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, Vpx promotes HIV infection of macrophages and PMA-differentiated THP-1 cells [12]. Vpx is packaged into budding virions via interaction with the p6 domain of Gag [13] and is active during the early steps of infection in the target cell [5].…”

Section: Introductionmentioning

confidence: 99%

SAMHD1-Deficient CD14+ Cells from Individuals with Aicardi-Goutières Syndrome Are Highly Susceptible to HIV-1 Infection

et al. 2011

View full text Add to dashboard Cite

Myeloid blood cells are largely resistant to infection with human immunodeficiency virus type 1 (HIV-1). Recently, it was reported that Vpx from HIV-2/SIVsm facilitates infection of these cells by counteracting the host restriction factor SAMHD1. Here, we independently confirmed that Vpx interacts with SAMHD1 and targets it for ubiquitin-mediated degradation. We found that Vpx-mediated SAMHD1 degradation rendered primary monocytes highly susceptible to HIV-1 infection; Vpx with a T17A mutation, defective for SAMHD1 binding and degradation, did not show this activity. Several single nucleotide polymorphisms in the SAMHD1 gene have been associated with Aicardi-Goutières syndrome (AGS), a very rare and severe autoimmune disease. Primary peripheral blood mononuclear cells (PBMC) from AGS patients homozygous for a nonsense mutation in SAMHD1 (R164X) lacked endogenous SAMHD1 expression and support HIV-1 replication in the absence of exogenous activation. Our results indicate that within PBMC from AGS patients, CD14+ cells were the subpopulation susceptible to HIV-1 infection, whereas cells from healthy donors did not support infection. The monocytic lineage of the infected SAMHD1 -/- cells, in conjunction with mostly undetectable levels of cytokines, chemokines and type I interferon measured prior to infection, indicate that aberrant cellular activation is not the cause for the observed phenotype. Taken together, we propose that SAMHD1 protects primary CD14+ monocytes from HIV-1 infection confirming SAMHD1 as a potent lentiviral restriction factor.

show abstract

Multifaceted activity of HIV Vpr/Vpx proteins: the current view of their virological functions

Cited by 33 publications

References 73 publications

HIV accessory proteins versus host restriction factors

HIV accessory proteins versus host restriction factors

How Samhd1 changes our view of viral restriction

SAMHD1-Deficient CD14+ Cells from Individuals with Aicardi-Goutières Syndrome Are Highly Susceptible to HIV-1 Infection

Contact Info

Product

Resources

About