vpr deletion mutant of simian immunodeficiency virus induces AIDS in rhesus monkeys

Hoch, James A.; Lang, Sabine M.; Weeger, M; Stahl–Hennig∥, Christiane; Coulibaly, Cheick; Dittmer, Ulf; Hunsmann, Gerhard; Fuchs, Dietmar; Müller, Judith; Sopper, Sieghart

doi:10.1128/jvi.69.8.4807-4813.1995

“…Since vpx and vpr share considerable sequence similarity and are juxtaposed in the HIV-2/SIVSM/SIVMAc genome, it has been suggested that they arose from a geneduplication event (Tristem et al, 1990). This, together with the finding that mutants of SIVMAC which lack functional vpx or vpr proteins retain their in vivo pathogenicity (Gibbs et al, 1995;Hoch et al, 1995), has been taken to suggest that the HIV-2/SIVSM/SIVMAc vpx and vpr genes have duplicative or at least overlapping functions (Gibbs et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Nuclear import and cell cycle arrest functions of the HIV-1 Vpr protein are encoded by two separate genes in HIV-2/SIV(SM).

Fletcher

¹

,

Břicháček

²

,

Sharova

³

et al. 1996

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The vpr genes of human and simian immunodeficiency viruses (HIV/SIV) encode proteins which are packaged in the virus particle. HIV‐1 Vpr has been shown to mediate the nuclear import of viral reverse transcription complexes in non‐dividing target cells (e.g. terminally differentiated macrophages), and to alter the cell cycle and proliferation status of the infected host cell. Members of the HIV‐2/SIV(SM) group encode, in addition to Vpr, a related protein called Vpx. Because these two proteins share considerable sequence similarity, it has been assumed that they also exhibit similar functions. Here, we report that the functions of Vpr and Vpx are distinct and non‐redundant, although both proteins are components of the HIV‐2/SIV(SM) virion and reverse transcription complex. Characterizing SIV(SM) proviruses defective in one or both genes, we found that Vpx is both necessary and sufficient for the nuclear import of the viral reverse transcription complex. In contrast, Vpr, but not Vpx, inhibited the progression of infected host cells from the G2 to the M phase of the cell cycle. Thus, two independent functions of the HIV‐1 Vpr protein are encoded by separate genes in HIV‐2/SIV(SM). This segregation is consistent with the conservation of these genes in HIV‐2/SIV(SM) evolution, and underscores the importance of both nuclear transport and cell cycle arrest functions in primate lentivirus biology.

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“…Vpr seems to be required at various steps of the HIV replication cycle and is therefore an interesting target for the development of antiviral agents. This 96-amino-acid protein is an important factor for the pathogenesis of HIV [1,2]. Vpr is an integral part of viral particles suggesting an important role in early stages of infection [3][4][5][6].…”

mentioning

confidence: 99%

Structure of human immunodeficiency virus type 1 Vpr(34–51) peptide in micelle containing aqueous solution

Engler

¹

,

Stangler

²

,

Willbold

³

2002

European Journal of Biochemistry

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Human immunodeficiency virus type 1 protein R (HIV-1 Vpr) promotes nuclear entry of viral nucleic acids in nondividing cells, causes G 2 cell cycle arrest and is involved in cellular differentiation and cell death. Vpr subcellular localization is as variable as its functions. It is known, that consistent with its role in nuclear transport, Vpr localizes to the nuclear envelope of human cells. Further, a reported ion channel activity of Vpr is clearly dependent on its localization in or at membranes. We focused our structural studies on the secondary structure of a peptide consisting of residues 34-51 of HIV-1 Vpr. This part of Vpr plays an important role in Vpr oligomerization, contributes to cell cycle arrest activity, and is essential for virion incorporation and binding to HHR23A, a protein involved in DNA repair. Employing NMR spectroscopy we found this part of Vpr to be almost completely a helical in the presence of micelles, as well as in trifluoroethanol containing and methanol/ chloroform solvent. Our results provide structural data suggesting residues 34-51 of Vpr to contain an amphipathic, leucine-zipper-like a helix, which serves as a basis for oligomerization of Vpr and its interactions with cellular and viral factors involved in subcellular localization and virion incorporation of Vpr.

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“…Vpr seems to be required at various steps of the HIV replication cycle and is therefore an interesting target for the development of antiviral agents. This 96-amino-acid protein is an important factor for the pathogenicy of HIV [1,2]. Vpr is an integral part of viral particles suggesting an important role in early stages of infection [3±6].…”

mentioning

confidence: 99%

Solution structure of human immunodeficiency virus type 1 Vpr(13-33) peptide in micelles

Engler¹,

Stangler²,

Willbold³

2001

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Human immunodeficiency virus type 1 protein R (HIV-1 Vpr) promotes nuclear entry of viral nucleic acids in nondividing cells, causes G 2 cell cycle arrest and is involved in cellular differentiation and cell death. Also, Vpr subcellular localization is as variable as its functions. It is known that, consistent with its role in nuclear transport, Vpr localizes to the nuclear envelope of human cells. Further, a reported ion channel activity of Vpr obviously is dependent on its localization in or at membranes. We focused our structural studies on the secondary structure of a peptide consisting of residues 13±33 of HIV-1 Vpr in micelles. Employing nuclear magnetic resonance and circular dichroism spectroscopy we found this part of Vpr, known to be essential for nuclear localization, to be almost completely a helical. Our results provide structural data suggesting residues 13±33 of Vpr to form an amphipathic, leucine-zipper-like a helix that serves as a basis for interactions with a variety of viral and cellular factors.Keywords: HIV-1; Vpr; peptide solution structure; dodecylphosphocholine; micelles.Human immunodeficiency virus type 1 (HIV-1) is a member of the lentivirus family. In addition to the gag, pol and env genes present in all retroviruses, HIV-1 encodes regulatory and accessory proteins, that are decisive for viral infectivity, replication and pathogenity. One of these proteins is virus protein R (Vpr). Vpr seems to be required at various steps of the HIV replication cycle and is therefore an interesting target for the development of antiviral agents. This 96-amino-acid protein is an important factor for the pathogenicy of HIV [1,2]. Vpr is an integral part of viral particles suggesting an important role in early stages of infection [3±6]. Furthermore, Vpr is involved in the transport of the preintegration complex into the host cell nucleus, which is an important feature for infection of nondividing cells [7,8] Recent structural studies of Vpr fragments by NMR were performed in trifluoroethanol (30%) containing solution and, not surprisingly, revealed a long amphipathic a helixturn-a helix (amino acids 17±46) motif ended by a turn for Vpr (1±51) [20]. The Vpr (52±96) fragment, also in trifluorethanol containing solution, is characterized by an amphipathic a helix from residue 53 to residue 78 and a less defined C-terminal domain [21]. Another fragment of Vpr (50±82) was shown to contain a helix from residues 53±81 in 50% trifluorethanol. Trifluorethanol, however, is well known to induce a helical secondary structures in peptides [22].We focused our structural studies on residues 13±33 of HIV-1 Vpr. This part of Vpr is known to be essential for ion chanel activity [15], cell cycle arrest [23], incorporation of Vpr into virus-like particles [24±26], and its nuclear localization [27]. Because a membranous or membranelike environment may be important for most of these activities, we carried out structural studies of Vpr(13±33) peptide in dodecylphosphocholine (dodecyl-PCho) containing micelles by CD and NMR sp...

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vpr deletion mutant of simian immunodeficiency virus induces AIDS in rhesus monkeys

Cited by 81 publications

References 32 publications

Nuclear import and cell cycle arrest functions of the HIV-1 Vpr protein are encoded by two separate genes in HIV-2/SIV(SM).

Nuclear import and cell cycle arrest functions of the HIV-1 Vpr protein are encoded by two separate genes in HIV-2/SIV(SM).

Structure of human immunodeficiency virus type 1 Vpr(34–51) peptide in micelle containing aqueous solution

Solution structure of human immunodeficiency virus type 1 Vpr(13-33) peptide in micelles

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