Human Immunodeficiency Virus<i>vpr</i>Gene Encodes a Virion-Associated Protein

Yuan, Xin; Matsuda, Zene; Matsuda, Michiko; Essex, Max; Lee, Tun‐Hou

doi:10.1089/aid.1990.6.1265

Cited by 124 publications

(91 citation statements)

References 38 publications

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“…To understand the role of HIV-1 accessory regulatory genes during HIV-1 replication and pathogenesis, we focused on the vpr gene product, which is a 96-aa protein produced late in the virus life cycle and assembled into the virion through binding to Gag (11)(12)(13). Function of Vpr appears to be critical for HIV-1 to replicate in macrophages (14).…”

Section: Hiv-1mentioning

confidence: 99%

Interaction of Virion Protein Vpr of Human Immunodeficiency Virus Type 1 with Cellular Transcription Factor Sp1 and trans-Activation of Viral Long Terminal Repeat

Wang

Mukherjee

Jia

et al. 1995

Journal of Biological Chemistry

161

113

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Acquired immunodeficiency syndrome (AIDS) is a result of replication of the human immunodeficiency virus type 1 (HIV-1) predominantly in CD4؉ T lymphocytes and macrophages. However, most of these cells in vivo are immunologically quiescent, a condition restricting HIV-1 replication. Vpr is an HIV-1 virion protein suspected to enhance HIV-1 replication in vivo. We demonstrate in this report that Vpr specifically activates HIV-1 long terminal repeat (LTR)-directed transcription. This effect is most pronounced on a minimal promoter from HIV-1 LTR containing the TATA box and binding motifs for the ubiquitous cellular transcription factor Sp1. Evidence is presented that Vpr interacts with Sp1 when Sp1 is bound to the Sp1 motifs within the HIV-1 LTR. Both Vpr-Sp1 interaction and Vpr trans-activation require a central Leu/Ile-rich domain in Vpr. Our findings suggest that Vpr trans-activation through Sp1 is most critical for the immediate early transcription of HIV-1 when other positive regulators, such as NF-B, are limited or inactive, a condition presumably present in vivo. By interacting with Sp1, Vpr also has the potential to influence cellular gene expression and cellular functions. Thus, therapeutic approaches directed toward blocking the Vpr trans-activation function could prove valuable in treating AIDS. HIV-11 is the etiological agent of AIDS. The hallmark of AIDS is the slow but progressive depletion of CD4 ϩ -T cells, a class of T cells crucial for immune functions. Depletion of CD4 ϩ -T cell results in immunodeficiency and AIDS-related disorders, including encephalopathy, dementia, and malignancies (1). Despite tremendous efforts in the past, the mechanism of these AIDS-related disorders has remained unclear. However, it is clear that these are a consequence of function of HIV-1 encoded gene products. For example, the HIV-1 envelope glycoprotein was implicated to be involved in toxic effects on neuronal cells (2). Recently, the HIV-1 Vpr protein in peripheral blood of HIV-1-infected people was shown to activate HIV-1 replication in latently infected cells (3,4). This effect of Vpr was suggested to contribute to HIV-1 pathogenesis in vivo.The HIV-1 genome encodes structural as well as regulatory gene products (5, 6). Recently, great efforts have been made toward understanding the function of the so-called accessory regulatory genes, namely vif, vpr, vpu, and nef. These genes are generally non-essential for HIV-1 to replicate in activated T cells. Yet, animal model studies with two of these genes, vpr and nef, suggested that they are required for in vivo replication and pathogenesis of the simian immunodeficiency virus (7,8). The paradox between HIV-1 replication in vitro and that in vivo suggests that HIV-1 replication may be subjected to different modes of regulation in vivo compared to in vitro. For example, in vitro studies have shown that HIV-1 replication is highly dependent on cellular activation and availability of activated NF-B transcription factor (5, 6, 9). However, in vivo, the majority of the sus...

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Section: Hiv-1mentioning

confidence: 99%

Interaction of Virion Protein Vpr of Human Immunodeficiency Virus Type 1 with Cellular Transcription Factor Sp1 and trans-Activation of Viral Long Terminal Repeat

Wang

Mukherjee

Jia

et al. 1995

Journal of Biological Chemistry

161

113

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“…Vpr has also been shown to increase gene expression non-specifically by threefold from a wide range of transcriptional promoters, by a mechanism that remains to be defined (Cohen et al, 1990a). The packaging of Vpr into the virions suggests that this protein plays an important role in virus assembly or infectivity (Cohen et al, 1990a;Yuan et al, 1990).…”

Section: Introductionmentioning

confidence: 99%

Particle assembly and Vpr expression in human immunodeficiency virus type 1-infected cells demonstrated by immunoelectron microscopy

Wang¹,

Lu²,

Ratner³

1994

Journal of General Virology

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“…Human immunoficiency virus type 1 (HIV-1) Vpr is a 96-amino-acid, 14-kDa protein that is expressed in infected cells in a Rev-dependent manner and is packaged into new virions through its interaction with the p6 region of the p55 gag precursor (6,51,75). While Vpr is clearly present in the HIV-1 virion, estimates on its abundance have varied from several hundred to as few as 18 Vpr molecules per viral particle (59).…”

mentioning

confidence: 99%

Nucleocytoplasmic Shuttling by Human Immunodeficiency Virus Type 1 Vpr

Sherman

Noronha

Heusch

et al. 2001

J Virol

109

106

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Human immunodeficiency virus type 1 (HIV-1) is capable of infecting nondividing cells such as macrophages because the viral preintegration complex is able to actively traverse the limiting nuclear pore due to the redundant and possibly overlapping nuclear import signals present in Vpr, matrix, and integrase. We have previously recognized the presence of at least two distinct and novel nuclear import signals residing within Vpr that, unlike matrix and integrase, bypass the classical importin ␣/␤-dependent signals and do not require energy or a RanGTP gradient. We now report that the carboxy-terminal region of Vpr (amino acids 73 to 96) contains a bipartite nuclear localization signal (NLS) composed of multiple arginine residues. Surprisingly, when the leucine-rich Vpr(1-71) fragment, previously shown to harbor an NLS, or full-length Vpr is fused to the C terminus of a green fluorescent protein-pyruvate kinase (GFP-PK) chimera, the resultant protein is almost exclusively detected in the cytoplasm. However, the addition of leptomycin B (LMB), a potent inhibitor of CRM1-dependent nuclear export, produces a shift from a cytoplasmic localization to a nuclear pattern, suggesting that these Vpr fusion proteins shuttle into and out of the nucleus. Studies of nuclear import with GFP-PK-Vpr fusion proteins in the presence of LMB reveals that both of the leucine-rich ␣-helices are required for effective nuclear uptake and thus define a unique NLS. Using a modified heterokaryon analysis, we have localized the Vpr nuclear export signal to the second leucine-rich helix, overlapping a portion of the amino-terminal nuclear import signal. These studies thus define HIV-1 Vpr as a nucleocytoplasmic shuttling protein.

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Human Immunodeficiency VirusvprGene Encodes a Virion-Associated Protein

Cited by 124 publications

References 38 publications

Interaction of Virion Protein Vpr of Human Immunodeficiency Virus Type 1 with Cellular Transcription Factor Sp1 and trans-Activation of Viral Long Terminal Repeat

Interaction of Virion Protein Vpr of Human Immunodeficiency Virus Type 1 with Cellular Transcription Factor Sp1 and trans-Activation of Viral Long Terminal Repeat

Particle assembly and Vpr expression in human immunodeficiency virus type 1-infected cells demonstrated by immunoelectron microscopy

Nucleocytoplasmic Shuttling by Human Immunodeficiency Virus Type 1 Vpr

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