HIV-1 Vpr: Regulator of Viral Survival

Thieu, Khanh; Morrow, Matthew P.; Shedlock, Devon J.; Schoenly, Kimberly A.; Mallilankaraman, Karthik; Choo, Andrew Y.; Fagone, Paolo; Weiner, David B.; Muthumani, Karuppiah

doi:10.2174/157016209787581454

Cited by 5 publications

(5 citation statements)

References 140 publications

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“…The virion-associated Vpr protein transactivates uDNA, enhancing expression of early viral proteins in infected activated CD4 ϩ T cells (28,29). Vpr has several other activities (30)(31)(32)(33), including the ability to arrest cell proliferation (34) in the G 2 /M phase of the cell cycle (35,36), which is favorable to HIV-1 transcription (37,38), as well as the capacity to enhance HIV-1 replication in nonproliferating cells (33,39,40), at least in part through assisting with viral nuclear import (30,41,42).…”

mentioning

confidence: 99%

An HIV-1 Replication Pathway Utilizing Reverse Transcription Products That Fail To Integrate

Trinité

Ohlson

Voznesensky

et al. 2013

J Virol

116

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cells. We found that infection of cytokine-treated resting CD4؉ T cells in the presence of raltegravir or with integrase active-site mutant HIV-1 yielded de novo virus production following subsequent T cell activation. Infection with integration-competent HIV-1 naturally generated a population of cells generating virus from unintegrated DNA. Latent infection persisted for several weeks and could be activated to virus production by a combination of a histone deacetylase inhibitor and a protein kinase C activator or by T cell activation. HIV-1 Vpr was essential for unintegrated HIV-1 gene expression and de novo virus production in this system. Bypassing integration by this mechanism may allow the preservation of genetic information that otherwise would be lost.

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mentioning

confidence: 99%

An HIV-1 Replication Pathway Utilizing Reverse Transcription Products That Fail To Integrate

Trinité

Ohlson

Voznesensky

et al. 2013

J Virol

116

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“…About two decades ago, a study in Jurkat T cells postulated a correlation between Vpr’s abilities to transactivate the LTR and cause G2 arrest [ 53 ]. Since then, multiple other studies on this topic have been carried out on immortalized cell lines, including T cell-derived models, where it was observed that Vpr-dependent transactivation relies on its capacity to recruit various isoforms of the Sp transcription factor family to the LTR [ 54 , 55 , 56 ], although this effect proved highly cell type-dependent. Only in 2019 did the work of Hotter and collaborators finally demonstrate the importance of Sp1 availability towards viral expression in the context of CD4 + T cells, though the role of Vpr in this process was not assessed in their study [ 57 ].…”

Section: Viral Genome Transcription and G2 Cell Cycle Arrestmentioning

confidence: 99%

“…Other work carried out in lymphocytic cell lines indicates that Vpr tethers the glucocorticoid receptor by mimicking the interaction with a steroid receptor coactivator (SRC), which induces it either to localize into the nucleus and into its binding site or to remain complexed in the cytosol in order for PARP-1 to be sequestered, thus preventing the latter from outcompeting Tat on its responsive element. Vpr was also seen to directly bind p300/CBP, itself an SRC proven to potentiate the effects of Tat [ 55 , 58 ]. However, again, these host cell interactions have never been functionally connected to G2 arrest in primary T cells.…”

Section: Viral Genome Transcription and G2 Cell Cycle Arrestmentioning

confidence: 99%

“…Liang and collaborators hinted at a link existing between Vpr-mediated cell cycle arrest and NF-κB translocation [ 114 ], with a novel study performed in macrophages indicating that Vpr-triggered DNA damage activates ATM, followed by the nuclear transport of various TFs, including NF-κB, CEBPB, and JUN [ 115 ]. Vpr’s capacity to interact with the SRC p300/CBP, until now only described in immortalized cell lines, did not only aid Tat’s transactivating role but was also accompanied by a significant increase in binding affinity between NF-κB and its LTR regulatory sequence [ 55 , 58 ].…”

Section: Signaling Disruption and Immune Evasionmentioning

confidence: 99%

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HIV-1 Vpr Functions in Primary CD4+ T Cells

Vanegas-Torres,

Schindler

2024

Viruses

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HIV-1 encodes four accesory proteins in addition to its structural and regulatory genes. Uniquely amongst them, Vpr is abundantly present within virions, meaning it is poised to exert various biological effects on the host cell upon delivery. In this way, Vpr contributes towards the establishment of a successful infection, as evidenced by the extent to which HIV-1 depends on this factor to achieve full pathogenicity in vivo. Although HIV infects various cell types in the host organism, CD4+ T cells are preferentially targeted since they are highly permissive towards productive infection, concomitantly bringing about the hallmark immune dysfunction that accompanies HIV-1 spread. The last several decades have seen unprecedented progress in unraveling the activities Vpr possesses in the host cell at the molecular scale, increasingly underscoring the importance of this viral component. Nevertheless, it remains controversial whether some of these advances bear in vivo relevance, since commonly employed cellular models significantly differ from primary T lymphocytes. One prominent example is the “established” ability of Vpr to induce G2 cell cycle arrest, with enigmatic physiological relevance in infected primary T lymphocytes. The objective of this review is to present these discoveries in their biological context to illustrate the mechanisms whereby Vpr supports HIV-1 infection in CD4+ T cells, whilst identifying findings that require validation in physiologically relevant models.

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“…Like MA, Vpr plays multiple roles in the replication cycle of HIV-1 [32][33][34][35][36][37][38]. In early infection, Vpr plays a key regulatory role in PIC nuclear import in macrophages [39][40][41].…”

Section: Viral Protein R (Vpr)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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HIV-1 Vpr: Regulator of Viral Survival

Cited by 5 publications

References 140 publications

An HIV-1 Replication Pathway Utilizing Reverse Transcription Products That Fail To Integrate

An HIV-1 Replication Pathway Utilizing Reverse Transcription Products That Fail To Integrate

HIV-1 Vpr Functions in Primary CD4+ T Cells

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

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