Understanding the mutual antagonism between HIV and autophagy
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Autophagy is a conserved cell survival pathway that is activated in response to stress to target cargo for lysosomal degradation. This pathway has recently gained attention as a potent mechanism of defense against viruses, since it can target virions and/or viral components to autophagosomes and halt virus replication. Furthermore, the autophagy-mediated breakdown of these viral structures facilitates (a) their engagement with endosomal pattern recognition receptors, and (b) their presentation through MHC-I/II molecules. Hence, besides its role in the direct elimination of viruses, autophagy also assists in shaping adaptive immune responses against these pathogens. Consistent with this, autophagy effectively protects from important infectious agents such as herpesviruses or flaviviruses. However, the role of autophagy in HIV infection remains controversial. Whereas some studies indicate that its degradative nature is detrimental for this virus, others have claimed that HIV triggers autophagy to increase its infectivity. Moreover, these contrasting findings seem to differ in a cell type-specific manner. Here, we show that autophagy restricts HIV replication through the clearance of the viral protein Gag, the main driver of virion assembly and release. Upon autophagy activation, Gag is targeted to autophagosomes for its subsequent degradation in autolysosomes. However, HIV has evolved its virulence factor Nef to protect from autophagy through a previously unappreciated mechanism. A thorough analysis of the interactions between HIV Nef and the autophagy machinery revealed that Nef enhances the association between the initiator of autophagy BECN1 and its natural inhibitor BCL2, impeding the early steps of autophagy and consequently autophagosome biogenesis. As a consequence of this, Gag levels and virion production are restored. Nef achieves this by promoting changes in the post-translational modification patterns of BCL2. In particular, HIV Nef recruits the E3 ubiquitin ligase PRKN to promote the mono-ubiquitination of BCL2. This post-translational modification renders BCL2 more stable and, thus, enhances its inhibitory effect over BECN1. Our structural analysis revealed that the N-terminal portion of Nef is responsible for this newly discovered anti-autophagic function. Remarkably, this ability of Nef to counteract autophagy is conserved in the most prevalent HIV-1 M subtypes as well as their direct ancestor SIVcpz, but largely missing in the HIV-2/SIVsm linage, which suggests that this activity has been a critical evolutionary trait for the pathogenesis and spread of HIV-1. In conclusion, autophagy poses an important hurdle for HIV, but the virus uses the nef gene – a notorious virulence factor that facilitates immune evasion – to counteract this block. Therefore, the identification of the cellular molecules targeted by Nef (i.e. BECN1-BCL2) represents an instrumental step to design approaches to make HIV susceptible to autophagy elimination.