Autophagy restricts HIV-1 infection

Human Immunodeficiency Virus type 1 (HIV-1) is a retrovirus that targets cells from the immune system such as the CD4 T lymphocytes, the macrophages and the dendritic cells (DCs). Although these host cells possess various defense mechanisms to fight this infection, HIV-1 has evolved multiple strategies to counteract them. For the past ten years, researchers have been focused on the identification of HIV-1 restriction factors and their mode of action for the development of new therapeutic strategies [1]. Macroautophagy (hereafter referred to as autophagy) is a major cellular catabolic pathway involved in several fundamental physiological processes, such as homeostasis, innate and adaptive immunities, development and differentiation. It is characterized by the formation of vacuoles called autophagosomes that sequester cytoplasmic constituents. The sequestered material is then degraded and recycled after fusion of autophagosomes with lysosomes. The autophagic pathway is orchestrated by more than thirty specific proteins named ATGs acting at different levels of the process [2]. Autophagy is believed to be one of the most ancient mechanism of defense against intracellular pathogens. Consequently, pathogens evolved strategies to prevent or hijack this process to their own benefit. Autophagy has long been considered as a bulk degradation pathway but it becomes clear that it is a highly selective process. The selectivity of its substrates is mediated by adaptor proteins, such as p62/SQSTM1, NDP52, NBR1 or Optineurin, which interact with ubiquitinated proteins and organelles, targeting specific cargos to autophagosomes [2]. We have demonstrated that HIV-1 envelope glycoproteins (Env), trigger autophagy at the very first step of CD4 T cells infection by their interaction with specific receptors (i.e. CD4 and CCR5 or CXCR4). This autophagic process exerts a powerful anti-HIV effect by selectively degrading the viral transactivator Tat (Transactivator of Transcription), a viral protein absolutely required for the transcription of viral genes. The selectivity of this degradation is conferred by p62/SQSTM1, which interacts with Tat independently of its ubiquitination [3]. Beside its role in transcriptional elongation of HIV genes, Tat is also secreted by infected cells and can be captured by neighboring uninfected cells where it activates the transcription of different cellular genes or induces their death by apoptosis. Interestingly, incoming Tat can also be degraded by autophagy, expanding the potential role of this mechanism beyond the viral replication itself. By selectively addressing Tat to lysosomal degradation, autophagy is a major anti-HIV pathway. The virus has thus evolved to avoid this powerful antiviral effect. Accordingly, …