Inhibition of human immunodeficiency virus type 1 (HIV-1) nuclear import via Vpr–Importin α interactions as a novel HIV-1 therapy

Suzuki, Tatsunori; Yamamoto, Norio; Nonaka, Mizuho; Hashimoto, Yoshie; Matsuda, Go; Takeshima, Shin‐nosuke; Matsuyama, Megumi; Igarashi, Tatsuhiko; Miura, Tomoyuki; Tanaka, Rie; Kato, Shingo; Aida, Yoko

doi:10.1016/j.bbrc.2009.01.180

Cited by 26 publications

(27 citation statements)

References 21 publications

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“…Nitahara-Kasahara et al (2007) reported that importin α (Imp-α) functions as a novel cellular factor for nuclear trafficking of Vpr. They further identified that hematoxylin, an inhibitor to the interaction of Imp-α and Vpr, attenuated the viral infection into macrophages (Suzuki et al 2009). As an interesting observation, we recently found that Vpr induces the retrotransposition of long interspersed nucleotide element 1 (L1) in a manner depending on the aryl hydrocarbon receptor (AhR; Okudaira et al, unpublished data).…”

Section: Discussionmentioning

confidence: 96%

Identification of SNF2h, a Chromatin-Remodeling Factor, as a Novel Binding Protein of Vpr of Human Immunodeficiency Virus Type 1

Taneichi

Iijima

Doi

et al. 2011

J Neuroimmune Pharmacol

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Vpr, an accessory gene of human immunodeficiency virus type 1, encodes a virion-associated nuclear protein that plays an important role in the primary viral infection of resting macrophages. It has a variety of biological functions, including roles in a cell cycle abnormality at G(2)/M phase, apoptosis, nuclear transfer of preintegration complex, and DNA double-strand breaks (DSBs), some of which depend on its association with the chromatin of the host cells. Given that DSB signals are postulated to be a positive factor in the viral infection, understanding the mode of chromatin recruitment of Vpr is important. Here, we identified SNF2h, a chromatin-remodeling factor, as a novel binding partner of Vpr involved in its chromatin recruitment. When endogenous SNF2h protein was extensively downregulated by SNF2h small interfering RNA (siRNA), the amount of Vpr loaded on chromatin decreased to about 30% of the control level. Biochemical analysis using a mutant Vpr suggested that Vpr binds SNF2h via HFRIG (amino acids 71-75 depicted by single letters) and the Vpr mutant lacking this motif lost the activity to induce DSB-dependent signals. Consistently, Vpr-induced DSBs were attenuated by extensive downregulaion of endogenous SNF2h. Based on these data, we discuss the role of DSB and DSB signals in the viral infection.

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Section: Discussionmentioning

confidence: 96%

Identification of SNF2h, a Chromatin-Remodeling Factor, as a Novel Binding Protein of Vpr of Human Immunodeficiency Virus Type 1

Taneichi

Iijima

Doi

et al. 2011

J Neuroimmune Pharmacol

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“…HIV-1 Vpr enhances the ability of HIV-1 to replicate in terminally differentiated macrophages, which is attributed to the activity of Vpr in active nuclear import of the virus PIC (Jenkins et al, 1998;Le Rouzic et al, 2002;Schang, 2003;Suzuki et al, 2009). The HIV-1 PIC is composed of viral proteins, such as Vpr, reverse transcriptase (RT), integrase (IN), nucleocapsid (NC) and matrix (MA), in addition to viral nucleic acids.…”

Section: Nuclear Import Of the Picmentioning

confidence: 99%

Human immunodeficiency virus type 1 Vpr: functions and molecular interactions

Romani

Engelbrecht

2009

Journal of General Virology

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Human immunodeficiency virus type 1 (HIV-1) viral protein R (Vpr) is an accessory protein that interacts with a number of cellular and viral proteins. The functions of many of these interactions in the pathogenesis of HIV-1 have been identified. Deletion of the vpr gene reduces the virulence of HIV-1 dramatically, indicating the importance of this protein for the virus. This review describes the current findings on several established functions of HIV-1 Vpr and some possible roles proposed for this protein. Because Vpr exploits cellular proteins and pathways to influence the biology of HIV-1, understanding the functions of Vpr usually involves the study of cellular pathways. Several functions of Vpr are attributed to the virion-incorporated protein, but some of them are attributed to the expression of Vpr in HIV-1-infected cells. The structure of Vpr may be key to understanding the variety of its interactions. Due to the critical role of Vpr in HIV-1 pathogenicity, study of the interactions between Vpr and cellular proteins may help us to understand the mechanism(s) of HIV-1 pathogenicity.

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“…The interaction between HIV-1 Vpr and importin is crucial not only for the nuclear import of Vpr but also for viral replication in macrophages [43]. Recently, hematoxylin (7) was identified as a new HIV-1 PIC nuclear import inhibitor that targets the Vpr-Importin interaction [74].…”

Section: Iti-367 (4)mentioning

confidence: 99%

Blocking Nuclear Import of Pre-Integration Complex: An Emerging Anti-HIV-1 Drug Discovery Paradigm

Zhan¹,

Liu²,

Clercq

2010

CMC

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Although recent progress in highly active antiretroviral therapy (HAART) has provided an effective way to treat AIDS patients, the emergence of drug-resistant HIV-1 strains and drug toxicity during long-term treatment of HIV-infected patients necessitate the search for new targets that can be used to develop novel antiviral agents. One such target is the nuclear import process of the HIV pre-integration complex (PIC). The ability of HIV-1 using host cell nuclear import machinery to translocate the viral PIC into the cell nucleus is the critical determinant in the replication of the virus in non-dividing cells, such as macrophages. Compounds inhibiting HIV-1 nuclear import may be attractive candidates for novel anti-HIV development. In this review, we will describe the mechanisms of HIV-1 PIC translocation into the nucleus and the structure-function of the viral and cellular factors involved in this process, as well as several classes of novel anti-HIV compounds which target the nuclear import of HIV-1 PIC and effectively block viral replication.

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Inhibition of human immunodeficiency virus type 1 (HIV-1) nuclear import via Vpr–Importin α interactions as a novel HIV-1 therapy

Cited by 26 publications

References 21 publications

Identification of SNF2h, a Chromatin-Remodeling Factor, as a Novel Binding Protein of Vpr of Human Immunodeficiency Virus Type 1

Identification of SNF2h, a Chromatin-Remodeling Factor, as a Novel Binding Protein of Vpr of Human Immunodeficiency Virus Type 1

Human immunodeficiency virus type 1 Vpr: functions and molecular interactions

Blocking Nuclear Import of Pre-Integration Complex: An Emerging Anti-HIV-1 Drug Discovery Paradigm

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