Transcriptional suppression of antiviral immune responses by HIV-1 Vpu

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The Human immunodeficiency virus 1 (HIV-1) is the causative agent of the acquired immunodeficiency syndrome (AIDS) and has infected more than 70 million people worldwide. Although humans are equipped with a variety of intrinsic, innate, and adaptive antiviral immune responses, HIV-1 has evolved sophisticated evasion strategies. Many of these strategies involve the viral accessory proteins Vpu, Nef, Vif and Vpr, which interfere with host factors to ensure efficient viral replication in vivo. While direct counteraction mechanisms have been investigated in detail, relatively little is known about transcriptional regulation, despite the fact that the latter may exert global effects on immune activation. As chronic immune activation is an important driver of disease progression in HIV infected individuals, a better understanding of how viral factors modulate host cell transcription will not only increase our understanding of the determinants of AIDS progression, but may ultimately also result in the identification of novel targets for therapy and prevention. The proposed projects focuses on the modulation of immune activation by the viral protein Vpu. Vpu was shown to efficiently block activation of the transcription factor NF-κB, a key regulator of innate and adaptive immune responses. I therefore hypothesize that Vpu is a potent transcriptional suppressor of antiviral immune responses. Notably, NF-κB activation levels also determine expression of HIV-1 genes and thus play an important role in viral latency and reactivation. I would therefore like to investigate the impact of NF-κB counteraction on immune activation and viral replication by combining different leading-edge systems biology approaches. First, I will perform next generation RNA-sequencing of primary CD4+ T cells infected with primary HIV-1 isolates to decipher the effects of HIV-1 Vpu on cellular gene expression, with a specific focus on genes involved in antiviral immune signaling. Second, I will use two innovative proteomics approaches to determine the global effects of Vpu on protein ubiquitination and degradation in order to identify novel cellular factors that are targeted by Vpu and elucidate the mechanisms underlying Vpu-mediated inhibition of NF-κB. Eventually, the identified hits will be validated and their relevance for immune activation, transcriptional regulation and viral replication will be tested. The results of this study will not only provide important insights into the factors determining immune activation and thus progression to AIDS, but may also advance current therapeutic approaches, in which NF-κB is targeted to reactivate and eliminate HIV-1 from latent reservoirs. In summary, this proposal aims at characterizing a unique pathway by which HIV-1 suppresses the antiviral immune response.