Accessory Regulatory Proteins of HIV-1 and Host Restriction Factors Interactions

Primate immunodeficiency viruses, including HIV-1, The presence of accessory genes are characteristic of them, such as vif, vpr, vpx, vpu, and nef. The current knowledge indicates that none of this lentiviral accessory proteins has enzymatic activity. These proteins interact with cellular ligands to either act as adaptation of 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 sequestration of the factors involved. The intrinsic antiviral factors that restrict viral replication in host cells are countered by accessory proteins the HIV-1 and other lentiviruses had acquired along their evolution. Abbreviations: HIV-1: Human Immunodeficiency Virus Type 1; SIV: Simian Immunodeficiency Virus; IFN: Interferon; GPI: Glycophosphatidylinositol; MHC-1: Major Histocompatibility Complex Class 1; CRLs: Cullin-Ring Ligases; Vpr: Viral Protein r; VprBP: Vpr Binding Protein

find that this virus contained several additional open reading frames. in addition to the prototypical retroviral gag, pol, and env genes; Collectively, they were termed accessory genes due to a lack of understanding of their biological functions. Viruses need to counteract intrinsic antiviral factors that restrict viral replication in host cells and for this purpose HIV and SIV might have acquired accessory proteins along their evolution. Virus protein U or Vpu is a lentiviral viroporin of 81 aminoacid, that is specific of HIV-1.This accessory protein is a membrane phosphoprotein, oligomeric with diversified biological functions. Vpu accessory protein is implicated in CD4 degradation, involving the ubiquitin proteasome pathway as well as in the release of virions from host cells. Viral infectivity factor or Vif is a highly conserved 23 kDa phosphoprotein, Vif is binded to the restriction factor APOBEG3AG which is cellular cytidine deaminases that provides inmmunity against HIV and promotes its degradation.
Vif is outstanding for the infectivity of HIV-1 virions that depends on the cell type. Vif is necessary to the synthesis of infectious virions in macrophages, lymphocytes, and dendritic cells expressing hA3G. Negative factor or Nef, is a membrane associated phosphoprotein with the N-terminal myristoylated. Nef is involved in many functions during the replication cycle of the VIH-1, therefore, it is believing that plays an important role in the increase virus infectivity and in cell apoptosis. Virus protein R or Vpr is a regulatory protein with nucleocytoplasmic shuttling. Vpr through the nuclear import of the preintegration complex play an important part in replication of the virus, Vpr also appears to cause its host cells to arrest their cell cycle in the G2 phase. Vpx is an HIV-2 and SIV encoded protein which functions are associated with Vpr. The HIV-1 is strictly adapted to human host. Cellular activation has been considered a requirement for HIV infection of CD4 T cells, as HIV fails to infect resting CD4 T cells from peripheral blood. Infection is aborted either during reverse transcription [1]. Like other primate retroviruses, the human immunodeficiency virus type 1 (HIV-1) is characterized by the presence of accessory genes, for example: vif, vpr, vpx, vpu, and nef. Current knowledge indicates that none of the primate lentiviral accessory proteins has enzymatic activity. Extensive studies on the underlying mechanism have revealed that Vif is one of viral accessory proteins, is critical for the HIV-1 species tropism in addition to Gag-capsid protein. Another auxiliary protein is Vpu that also has been demonstrated that affects this HIV-1 property.
The restriction factors are multitaskers and highly conserved, one of the restriction factors function is the regulation of cross-species infections. Consequently, in their natural hosts. they are less effective against viruses.

Vif (Viral Infectivity Factor) and APOBEC3G
APOBEC are a family of cellular cytidine deaminases and represent a group of proteins recently identified. APOBEC protect the cell from endogenous mobile retro elements and provide immunity against infection by retroviruses. Vif is an accessory protein of HIV-1 required for productive infectivity of T-lymphocytes, macrophages and dendritic cells expressing hA3G [2][3][4][5]. Vif plays a fundamental roll in the viral replication, is a protein of 23 kD that inhibits the host cell protein APOBECG3G (hA3G), which is a host defense factor human. Vif binding to hA3G since the viral entry prevents the assembly with viral particles and also mediates by the proteosomal pathway elimination through ubiquitination and degradation. hA3G

Nef and SERINC3, SERINC5
Nef (Negative Regulatory Factor) is a smal myristoylated protein of 27-35 kDa that is encoded by primate lentiviruses. These could prevent the entry of the virus prior to small pore formation by promoting structural changes in envelope glycoproteins [32].
Nef antagonize the antiviral activity of SERINC5, leading to a decrease in its incorporation in the virions, because Nef removes it from the plasma membrane and sequesters it in the endosomes for its subsequent degradation [33]. Nef induces,by using the cellular transport machinery, downregulation of SERINC3 and SERINC5 from the cell membrane, mainly using the trans-Golgi network and the endolysosomal system, in a mechanism similar to that used for CD4 downregulation [34][35][36].
Myristoylation requires Nef to anchor in the membrane for a posttranslational change and execute sequestration of the proteins [37,38].

Vpr (Viral Protein R) and VprBP (DCAF1)
The HIV protein, Vpr is critical for efficient viral infection of target CD4+ T cells and macrophages, it is a multifunctional accessory protein. Vpr is a 96 amino acid 14-kDa protein [39,40], Lentiviruses such as HIV-1, however, are unique among retroviruses where they are able to infect non-dividing cells [41,42].
Vpr protein shuttles between cytoplasm and nucleus once the virion enters the cell, to facilitate viral replication and, at late stages in the virus life cycle, newly synthesized Vpr is exported from the cell.
Two forms of nuclear Vpr have been observed, monomers and very large complexes, 1000× larger than a monomer. One of the outstanding activities performed by Vpr is the blockade of the cell cycle at G2 after HIV-1 infection of dividing cells [43][44][45][46]. The viral LTR promoter is more active in the phase G2 of the cell cycle. Other activities of Vpr include the transcriptional modulation of immune function and the regulation of apoptosis [47][48][49][50]. Several proteomic analyses have been undertaken in an attempt to unravel the precise mechanism of action of HIV-1 Vpr. There are changes induced by Vpr to protein modulators and mediators of signaling pathways related to glycolysis and other energy processes, involved in cell cycle, cell death and DNA repair, mitochondrial activity and redox homeostasis,. Cullin-RING ligases (CRLs) comprise a large group of modular eukaryotic E3 ubiquitin ligases. DCAF1 was originally discovered as the cellular target of the HIV-1 accessory protein viral protein r (Vpr), hereafter was originally named Vpr binding protein (VprBP) [51]. The substrate receptors for CRL4 have been termed DDB1 and CUL4-associated factors (DCAFs). The number of identified and putative DCAFs is in excess of 50 members and is likely to continue growing.

Conclusion
A fundamental concept to the biology of restriction factors is that cells, thereby allowing virus replication to proceed efficiently.