The PI3K/Akt Pathway in Herpesvirus Biology: A Double-Edged Sword in Host–Virus Interactions

TL;DR

This paper reviews how human herpesviruses manipulate the PI3K/Akt pathway to aid their replication, survival, and cancer development, while also exploring potential treatments targeting this pathway.

Contribution

The paper offers a comparative analysis of PI3K/Akt pathway manipulation across all eight human herpesviruses, emphasizing shared and virus-specific strategies.

Findings

Herpesviruses manipulate the PI3K/Akt pathway at multiple stages of their life cycle to promote replication and immune evasion.

Sustained PI3K/Akt signaling is linked to latency and oncogenesis in Epstein–Barr virus and Kaposi’s sarcoma-associated herpesvirus.

Targeting the PI3K/Akt pathway is proposed as a host-directed antiviral and anticancer strategy.

Abstract

Human herpesviruses (HHVs) are notorious, ubiquitous intracellular pathogens that establish lifelong infections in the host. They tightly manipulate host signaling pathways that play central roles in key cellular processes such as cell survival, metabolism, immune responses, and oncogenic transformation. Among the many pathways explored, the phosphatidylinositol-3-kinase (PI3K)/Akt signaling axis has emerged as a central and conserved target exploited by all eight HHVs. Herpesviruses can induce PI3K/Akt signaling at multiple stages of their life cycle, beginning at viral entry and extending through lytic replication, latency maintenance, immune evasion, and virus-associated tumorigenesis. Mechanistically, herpesviruses engage both host cell receptors and viral effector proteins to activate PI3K, drive Akt phosphorylation, and thereby orchestrate downstream signaling pathways that favor viral replication, survival, and immune evasion. Transient activation of this pathway supports viral replication, whereas sustained signaling promotes latent infection and oncogenesis, particularly in Epstein–Barr virus and Kaposi’s sarcoma-associated herpesvirus. This review provides a comparative analysis of PI3K/Akt pathway manipulation across all HHVs, highlighting shared strategies and virus-specific adaptations. We further discuss ongoing clinical trials and therapeutic opportunities targeting the PI3K/Akt axis, emphasizing its potential as a host-directed antiviral and anticancer strategy.

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