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HIV-1 Vpu is a potent transcriptional suppressor of NF-?B-elicited antiviral immune responses.

ABSTRACT: Many viral pathogens target innate sensing cascades and/or cellular transcription factors to suppress antiviral immune responses. Here, we show that the accessory viral protein U (Vpu) of HIV-1 exerts broad immunosuppressive effects by inhibiting activation of the transcription factor NF-?B. Global transcriptional profiling of infected CD4 +T cells revealed that vpu-deficient HIV-1 strains induce substantially stronger immune responses than the respective wild type viruses. Gene set enrichment analyses and cytokine arrays showed that Vpu suppresses the expression of NF-?B targets including interferons and restriction factors. Mutational analyses demonstrated that this immunosuppressive activity of Vpu is independent of its ability to counteract the restriction factor and innate sensor tetherin. However, Vpu-mediated inhibition of immune activation required an arginine residue in the cytoplasmic domain that is critical for blocking NF-?B signaling downstream of tetherin. In summary, our findings demonstrate that HIV-1 Vpu potently suppresses NF-?B-elicited antiviral immune responses at the transcriptional level.

SUBMITTER: Langer S

PROVIDER: S-EPMC6372280 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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HIV-1 Vpu is a potent transcriptional suppressor of NF-κB-elicited antiviral immune responses.

Langer Simon S Hammer Christian C Hopfensperger Kristina K Klein Lukas L Hotter Dominik D De Jesus Paul D PD Herbert Kristina M KM Pache Lars L Smith Nikaïa N van der Merwe Johannes A JA Chanda Sumit K SK Fellay Jacques J Kirchhoff Frank F Sauter Daniel D

eLife 20190205

Many viral pathogens target innate sensing cascades and/or cellular transcription factors to suppress antiviral immune responses. Here, we show that the accessory viral protein U (Vpu) of HIV-1 exerts broad immunosuppressive effects by inhibiting activation of the transcription factor NF-κB. Global transcriptional profiling of infected CD4 +T cells revealed that <i>vpu</i>-deficient HIV-1 strains induce substantially stronger immune responses than the respective wild type viruses. Gene set enric ...[more]

PMID: 30717826

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Project description:UnlabelledCharacterizing the cellular factors that play a role in the HIV replication cycle is fundamental to fully understanding mechanisms of viral replication and pathogenesis. Whole-genome small interfering RNA (siRNA) screens have identified positive and negative regulators of HIV replication, providing starting points for investigating new cellular factors. We report here that silencing of the deubiquitinase cylindromatosis protein (CYLD), increases HIV infection by enhancing HIV long terminal repeat (LTR)-driven transcription via the NF-κB pathway. CYLD is highly expressed in CD4(+) T lymphocytes, monocyte-derived macrophages, and dendritic cells. We found that CYLD silencing increases HIV replication in T cell lines. We confirmed the positive role of CYLD silencing in HIV infection in primary human CD4(+) T cells, in which CYLD protein was partially processed upon activation. Lastly, Jurkat T cells latently infected with HIV (JLat cells) were more responsive to phorbol 12-myristate 13-acetate (PMA) reactivation in the absence of CYLD, indicating that CYLD activity could play a role in HIV reactivation from latency. In summary, we show that CYLD acts as a potent negative regulator of HIV mRNA expression by specifically inhibiting NF-κB-driven transcription. These findings suggest a function for this protein in modulating productive viral replication as well as in viral reactivation.ImportanceHIV transcription is regulated by a number of host cell factors. Here we report that silencing of the lysine 63 deubiquitinase CYLD increases HIV transcription in an NF-κB-dependent manner. We show that CYLD is expressed in HIV target cells and that its silencing increases HIV infection in transformed T cell lines as well as primary CD4(+) T cells. Similarly, reactivation of latent provirus was facilitated in the absence of CYLD. These data suggest that CYLD, which is highly expressed in CD4(+) T cells, can control HIV transcription in productive infection as well as during reactivation from latency.

Dataset Information

HIV-1 Vpu is a potent transcriptional suppressor of NF-?B-elicited antiviral immune responses.

Publications

HIV-1 Vpu is a potent transcriptional suppressor of NF-κB-elicited antiviral immune responses.

Similar Datasets

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