講演要旨

The human immunodeficiency virus type I (HIV-1) has evolved sophisticated means to evade or counteract antiviral immune responses. For example, HIV-1 targets innate cellular restriction factors for degradation and down-modulates CD4, MHC-I and other surface receptors regulating adaptive immunity to ensure efficient viral replication. While most immune evasion strategies involve direct interactions with cellular antiviral proteins, we have recently shown that the accessory viral protein U (Vpu) prevents activation of the transcription factor NF-κB (Sauter et al., Cell Reports, 2015), suggesting that HIV-1 may suppress immune activation also on a transcriptional level.

To analyze the effects of Vpu on cellular gene expression in a broad and unbiased manner, we therefore performed global transcriptome analyses of CD4+ T cells infected with primary HIV-1 constructs containing wild-type or mutated vpu genes. Network analyses of differentially expressed genes showed that Vpu efficiently suppresses the expression of a variety of NF-κB target genes. In agreement with a key role of NF-κB in immunity, Vpu significantly decreased the expression of interferons (IFNs) and IFN-stimulated genes (ISGs). Furthermore, gene set enrichment analyses revealed that MHC-I antigen presentation, sensing of viral nucleic acids and expression of restriction factors such as IFIT1-3, MX1 and APOBEC3B were also significantly reduced by Vpu.

In summary, these findings establish HIV-1 Vpu as a key suppressor of antiviral immune responses and add to the accumulating evidence that lentiviral accessory proteins modulate the immune system also on a transcriptional level.