br Concluding remarks Autophagy ensures cell homeostasis and

Concluding remarks Autophagy ensures cell homeostasis and survival through the continuous degradation/recycling of intracellular components. It can also represent a conserved, cell-intrinsic, defense mechanism against invading pathogens, including viruses. The autophagy process can be activated rapidly upon attachment/entry of viruses. Both surface receptor engagement by viral factors and membrane perturbations caused by viral PF-04691502 appear able to mediate such activation. Within cells, autophagy activation can be initiated upon detection of viral nucleic acids by specialized cytosolic sensors: autophagy induction can be coupled not only to receptors that trigger transcription-dependent anti-viral programs but also to engagement of receptors involved in direct targeting of viral products. In many instances, the exact molecular events involved are not elucidated and require further investigations. Autophagy is susceptible to target entire viral particles or viral constituents for degradation, thereby contributing to virus restriction and in some cases, to initiation of anti-viral innate immune responses. In virally infected cells, autophagy can both contribute to induction of anti-viral responses, such as production of IFN-I or inflammatory cytokines, and subsequently attenuate these responses by targeting key factors involved in their inducing pathways in order to limit immunopathology. Many viruses evolved strategies to interfere with the functional links that exists between the autophagy process and anti-viral response pathways. Such interferences allow them to down-regulate the production of anti-viral cytokines. Internalized viruses can also manipulate host factors to escape sequestration within autophagosomes. In some cases, the manipulation combines interference with autophagic targeting with utilization of autophagic factors to promote their life cycle. Most of these effects remain to be fully characterized with respect to the fine molecular mechanisms involved (Fig. 3).
Perspectives As detailed in this article, many viruses exert a substantial influence on the autophagy machinery during the early stages of their interaction with host cells. The corpus of available information on these influences raises a number of questions. Independently of signaling events directly associated to cellular receptors engagement, autophagy can be induced by membrane perturbations taking place at the plasma membrane or endosomal membrane. As mentioned above, the HIV-1 envelope glycoprotein gp41 can induce autophagy due to its fusogenic property rather than to signaling events associated to interaction with CD4 or CXCR4 [51]. Formation of multinucleated giant cells driven by viral glycoprotein-mediated fusion also appears as a source of efficient autophagy induction. This phenomenon, which has been reported for infection by two paramyxoviruses, MeV and canine distemper virus [40], [114], is currently not understood. Possibly, the sensing of membrane physical changes may represent an important pathway for rapid autophagy induction. Membrane fusion involved in enveloped virus entry proceeds in several steps that comprise hemifusion, pore formation and pore enlargement. Whether events associated with these steps could be sensed by the autophagy machinery is unknown. As to non-enveloped viruses, the mechanisms used to penetrate membranes are not well understood but necessarily involve substantial membrane modifications as well. Thus, whether membrane destabilization phenomena associated with virus entry can represent an autophagy-inducing event per se should be explored. Data on adenovirus and picornaviruses revealing the viral manipulation of Nedd.4 and PLA2G16 host factors, respectively, at the time of endosomal membrane fragmentation illustrate how efficient the subversion of cellular components by entering viruses can be for the avoidance of Galectin 8-associated antiviral autophagic responses. Further work is needed to detail the molecular events involved in such host factor manipulations and the rules that govern them. It is also of interest to estimate to which extend host factor subversion is a frequent strategy adopted by viruses to resist anti-viral autophagy and define which principles have been operating for its emergence during evolution. With respect to adenovirus, we have seen that neutralization of capsid sequestration by autophagosome is coupled to exploitation of the autophagy machinery for capsid escape from endosomes, microtubule-dependent transport and appropriate genome delivery to the nucleus [97]. As this recent work pointed to a possible role for LC3 in stabilizing the capsid–motor interaction and promoting the retrograde trafficking to the nucleus, further investigations are necessary to identify the kinetic and mechanism of LC3 recruitment to the capsid–motor complex. Whether Nedd4.2 plays a role in such a recruitment needs to be explored as well. Finally, as adenovirus manipulation of autophagy might be advantageous to many viruses whose replication cycle requires genome delivery into host cell nucleus, it will be of interest to determine whether other model viruses behave similarly.