HIV-1 Vpr N-terminal tagging affects alternative splicing of the viral genome

Baeyens, Ann; Naessens, Evelien; Nuffel, Anouk Van; Weening, Karin; Reilly, Anne-Marie; Claeys, Eva; Trypsteen, Wim; Vandekerckhove, Linos; Eyckerman, Sven; Gevaert, Kris; Verhasselt, Bruno

doi:10.1038/srep34573

Cited by 9 publications

(9 citation statements)

References 52 publications

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“…This defect, however, could be rescued by pseudotyping the virions with the vesicular stomatitis virus glycoprotein (VSV-G) ( S4A Fig ). Unfortunately, however, the IMCs encoding SIVcol CGU1, CM243 and CM1437 vpr remained non-infectious, possibly due to the disruption of splice sites regulating Tat expression [ 29 ], and could therefore not be used for infection studies.…”

Section: Resultsmentioning

confidence: 99%

Primate lentiviruses use at least three alternative strategies to suppress NF-κB-mediated immune activation

et al. 2017

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Primate lentiviruses have evolved sophisticated strategies to suppress the immune response of their host species. For example, HIV-2 and most simian immunodeficiency viruses (SIVs) use their accessory protein Nef to prevent T cell activation and antiviral gene expression by downmodulating the T cell receptor CD3. This Nef function was lost in HIV-1 and other vpu-encoding viruses suggesting that the acquisition of Vpu-mediated NF-κB inhibition reduced the selection pressure for inhibition of T cell activation by Nef. To obtain further insights into the modulation of NF-κB activity by primate lentiviral accessory factors, we analyzed 32 Vpr proteins from a large panel of divergent primate lentiviruses. We found that those of SIVcol and SIVolc infecting Colobinae monkeys showed the highest efficacy in suppressing NF-κB activation. Vpr-mediated inhibition of NF-κB resulted in decreased IFNβ promoter activity and suppressed type I IFN induction in virally infected primary cells. Interestingly, SIVcol and SIVolc differ from all other primate lentiviruses investigated by the lack of both, a vpu gene and efficient Nef-mediated downmodulation of CD3. Thus, primate lentiviruses have evolved at least three alternative strategies to inhibit NF-κB-dependent immune activation. Functional analyses showed that the inhibitory activity of SIVolc and SIVcol Vprs is independent of DCAF1 and the induction of cell cycle arrest. While both Vprs target the IKK complex or a factor further downstream in the NF-κB signaling cascade, only SIVolc Vpr stabilizes IκBα and inhibits p65 phosphorylation. Notably, only de-novo synthesized but not virion-associated Vpr suppressed the activation of NF-κB, thus enabling NF-κB-dependent initiation of viral gene transcription during early stages of the replication cycle, while minimizing antiviral gene expression at later stages. Our findings highlight the key role of NF-κB in antiviral immunity and demonstrate that primate lentiviruses follow distinct evolutionary paths to modulate NF-κB-dependent expression of viral and antiviral genes.

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Section: Resultsmentioning

confidence: 99%

Primate lentiviruses use at least three alternative strategies to suppress NF-κB-mediated immune activation

et al. 2017

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“…HIV-1 encodes ten genes with different functions to sustain viral replication and infection [ 94 ]. Extensive research of HIV-1 alternative splicing has elucidated numerous spliced variants involved in viral protein transcription and regulation of splicing events [ 94 , 95 , 96 , 97 , 98 , 99 ]. Through extensive alternative splicing of a primary transcript, HIV-1 produces numerous mRNA isoforms to express viral proteins from nine genes: gag, pol, vif, vpr, vpu, env, nef, rev and tat.…”

Section: Virally-induced Alternative Splicing and Epigenetic Regulmentioning

confidence: 99%

Aberrant Splicing Events and Epigenetics in Viral Oncogenomics: Current Therapeutic Strategies

Francies

Dlamini

2021

Cells

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Global cancer incidence and mortality are on the rise. Although cancer is fundamentally a non-communicable disease, a large number of cancers are known to have a viral aetiology. A high burden of infectious agents (Human immunodeficiency virus (HIV), human papillomavirus (HPV), hepatitis B virus (HBV)) in certain Sub-Saharan African countries drives the rates of certain cancers. About one-third of all cancers in Africa are attributed to infection. Seven viruses have been identified with carcinogenic characteristics, namely the HPV, HBV, Hepatitis C virus (HCV), Epstein–Barr virus (EBV), Human T cell leukaemia virus 1 (HTLV-1), Kaposi’s Sarcoma Herpesvirus (KSHV), and HIV-1. The cellular splicing machinery is compromised upon infection, and the virus generates splicing variants that promote cell proliferation, suppress signalling pathways, inhibition of tumour suppressors, alter gene expression through epigenetic modification, and mechanisms to evade an immune response, promoting carcinogenesis. A number of these splice variants are specific to virally-induced cancers. Elucidating mechanisms underlying how the virus utilises these splice variants to maintain its latent and lytic phase will provide insights into novel targets for drug discovery. This review will focus on the splicing genomics, epigenetic modifications induced by and current therapeutic strategies against HPV, HBV, HCV, EBV, HTLV-1, KSHV and HIV-1.

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“…These mRNA variants (gag, pol, vif, vpr, vpu, env, nef, rev and tat) are important for the expression of the HIV protein isoforms. These HIV distinct isoforms may exist in full form, intron-lacking variants and intron-comprising variants [ 50 , 51 , 52 , 53 ]. Strict alternative splicing of these isoforms is crucial for the HIV life cycle and infection.…”

Section: Alternative Splicingmentioning

confidence: 99%

The Catastrophic HPV/HIV Dual Viral Oncogenomics in Concert with Dysregulated Alternative Splicing in Cervical Cancer

Marima

Hull

Lolas

et al. 2021

IJMS

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Cervical cancer is a public health problem and has devastating effects in low-to-middle-income countries (LTMICs) such as the sub-Saharan African (SSA) countries. Infection by the human papillomavirus (HPV) is the main cause of cervical cancer. HIV positive women have higher HPV prevalence and cervical cancer incidence than their HIV negative counterparts do. Concurrent HPV/HIV infection is catastrophic, particularly to African women due to the high prevalence of HIV infections. Although various studies show a relationship between HPV, HIV and cervical cancer, there is still a gap in the knowledge concerning the precise nature of this tripartite association. Firstly, most studies show the relationship between HPV and cervical cancer at genomic and epigenetic levels, while the transcriptomic landscape of this relationship remains to be elucidated. Even though many studies have shown HPV/HIV dual viral pathogenesis, the dual molecular oncoviral effects on the development of cervical cancer remains largely uncertain. Furthermore, the effect of highly active antiretroviral therapy (HAART) on the cellular splicing machinery is unclear. Emerging evidence indicates the vital role played by host splicing events in both HPV and HIV infection in the development and progression to cervical cancer. Therefore, decoding the transcriptome landscape of this tripartite relationship holds promising therapeutic potential. This review will focus on the link between cellular splicing machinery, HPV, HIV infection and the aberrant alternative splicing events that take place in HIV/HPV-associated cervical cancer. Finally, we will investigate how these aberrant splicing events can be targeted for the development of new therapeutic strategies against HPV/HIV-associated cervical cancer.

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HIV-1 Vpr N-terminal tagging affects alternative splicing of the viral genome

Cited by 9 publications

References 52 publications

Primate lentiviruses use at least three alternative strategies to suppress NF-κB-mediated immune activation

Primate lentiviruses use at least three alternative strategies to suppress NF-κB-mediated immune activation

Aberrant Splicing Events and Epigenetics in Viral Oncogenomics: Current Therapeutic Strategies

The Catastrophic HPV/HIV Dual Viral Oncogenomics in Concert with Dysregulated Alternative Splicing in Cervical Cancer

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