All roads lead to Akt: how HCMV controls Akt activity to generate a microenvironment favoring viral dissemination

Abstract

Infection with human cytomegalovirus (HCMV) is highly prevalent, with seropositivity reaching 80% in developed countries and upwards of 100% in developing countries. Because of the obligate intracellular nature, similar to other viruses, HCMV modulates cellular environment to promote infection. The Phosphatidylinositol-3-kinase (PI3K)/Akt pathway is modulated by many viruses because of its central importance in multiple cellular processes. HCMV has been reported to regulate Akt activity during all three stages of its lifecycle: quiescent, latent, and lytic infection. Previously, our lab showed that HCMV promotes Akt phosphorylation preferentially at serine 473 (S473) during quiescent infection to promote monocyte survival and hematogenous dissemination of the virus. This is in contrast to growth factor-mediated survival of monocytes which involves Akt phosphorylation at both S473 and threonine 308 (T308). The exact mechanism how HCMV induces an atypical Akt activation in monocytes, and its biological significance remains unclear. The studies in this thesis reveal that HCMV glycoproteins gB and gH work in concert to initiate a HCMV-specific signalosome responsible for a robust Akt activation through phosphorylation at S473 in monocytes. Moreover, we demonstrate that virion-associated US28-mediated signaling is required to inhibit Akt phosphorylation at T308. Induction of the atypical Akt activation is essential to establish HCMV quiescent infection and monocyte survival which are required for successful dissemination of the virus. We found that HCMV phosphorylates Akt at both S473 and T308 during viral entry into fibroblasts. However, with the progression of infection, HCMV suppresses Akt phosphorylation at both residues for efficient viral genome replication. Overall, our data demonstrate that HCMV regulates Akt activity in a multifaceted approach which depends on the type of infection to generate a microenvironment favoring viral infection and dissemination.