The herpes simplex virus-1 (HSV1) establishes latent neural infection and can be reactivated by poorly defined changes in immune system function or physiological factors. Nerve growth factor (NGF)–mediated signaling through phosphoinositide 3-kinase (PI3K) and Akt is required for maintaining HSV1 latency and suppressing lytic growth. Kobayashi et al. report that these kinases act through the mechanistic target of rapamycin complex 1 (mTORC1) to maintain latency. In cultured rat sympathetic neurons latently infected with HSV1, perturbation of signaling through mTORC1 by treatment of the cells with the pharmacological inhibitors PP242 or rapamycin or by depleting the cells of the mTORC1 subunit raptor with RNA interference (RNAi) increased the frequency of spontaneous reactivation and production of infectious viruses. Inhibiting mTORC1 signaling prevented mTORC1-mediated phosphorylation and inhibition of the translational repressor 4E-BP and caused the accumulation of a viral transcript required for lytic activation (ICP27). Pharmacological inhibitors of the mTORC1 activators PI3K (LY294002) and Akt (AKT VIII) also induced accumulation of ICP27. Rheb is a guanosine triphosphatase (GTPase) that activates mTORC1 downstream of PI3K and Akt, and expression of a lentivirus-encoded Rheb mutant that constitutively activates mTORC1 suppressed viral reactivation induced by LY294002 and by AKT VIII. This Rheb mutant did not prevent rapamycin-induced viral reactivation, because rapamycin acts on mTORC1 downstream of Rheb. Maintenance of latency requires continuous protein synthesis, and hypoxia disrupts protein synthesis by preventing mTORC1-mediated inhibition of 4E-BP. Culturing latently infected neurons under hypoxic conditions promoted HSV1 reactivation, indicating that environmental factors that affect mTORC1 signaling could influence viral latency. A version of 4E-BP that could not be inactivated by mTORC1 suppressed global protein translation and induced viral reactivation. Using a compartmentalized culture system in which axons and cell bodies could be individually manipulated, the authors demonstrated that applying the mTORC1 inhibitor PP242 to axons had no effect on 4E-BP phosphorylation status in the cell body but did inhibit 4E-BP phosphorylation and promote viral reactivation in the axon. These findings show that mTORC1 activity is important for maintaining HSV1 latency by suppressing 4E-BP–dependent translation in axons and imply that environmental factors that decrease mTORC1 signaling could be responsible for triggering reactivation under conditions of stress. Whether this mechanism is specific to HSV1 or applies to other viruses that can reactivate from latent infections remains to be seen.
M. Kobayashi, A. C. Wilson, M. V. Chao, I. Mohr, Control of viral latency in neurons by axonal mTOR signaling and the 4E-BP translation repressor. Genes Dev. 26, 1527–1532 (2012). [Abstract] [Full Text]