Hypoxia and viral infectious diseases

Abstract

Oxygen-sensing mechanisms allow cells to adapt and respond to changes in cellular oxygen tension, including hypoxic conditions. Hypoxia-inducible factor (HIF) is a central mediator in this fundamental adaptive response, and has critical functions in normal and disease physiology. Viruses have been shown to manipulate HIFs during their life cycle to facilitate replication and invasion. Conversely, HIFs are also implicated in the development of the host immune system and response to viral infections. Here, we highlight the recent revelations of host-pathogen interactions that involve the hypoxic response pathway and the role of HIF in emerging viral infectious diseases, as well as discussing potential antiviral therapeutic strategies targeting the HIF signaling axis.

Figure 1. The canonical oxygen-sensing pathway involving HIF.

HIF-1α is regulated through an oxygen-dependent mechanism that involves the hydroxylation of proline residues by PHDs and essential cofactors (including α-ketoglutarate and iron). Afterward, the E3 ubiquitin ligase complex (comprising VHL, Elongin B/C [EloB/C], Cul2, Rbx1, and E2) ubiquitinates HIF-1α, which results in its proteasomal degradation. However, under hypoxic conditions, PHDs are unable to perform their function, and HIF-1α is able to associate with HIF-1β within the nucleus to initiate the transcriptional responses for hypoxic adaptation.

Figure 2. The involvement of HIF in viral pathogenesis and host responses.

HIF can be involved in various viral mechanisms of infection and in the host antiviral response. Certain viruses can manipulate the HIF pathway by inhibiting the degradation of HIF-α that leads to HIF stabilization, which may result in cellular responses to increase viral replication and downregulate antiviral responses. Conversely, HIF plays a central role in immune responses against viruses by contributing to the development of B cells in germinal centers through T cell help, regulation of immune cell differentiation, and production of high-affinity antibodies. These actions of HIF reveal its duality in participating in both an antiviral and a propathogenic response.

Figure 3. Therapeutic methods targeting HIF to inhibit viral replication.

HIF stabilizers and inhibitors can act on various pathways involved in HIF signaling — such as HIF-α stabilization, ribosomal translation, mRNA expression levels, protein degradation, transcription, and binding to HREs — in order to disrupt the viral replicative life cycle. These different strategies depend on the role of HIF in either disrupting or assisting in infection and replication, which is dependent on the type of virus. Viruses such as HCV can manipulate the HIF response, whereas others, such as VSV, are inhibited. This highlights the need for further investigation in order to determine the role of HIF in facilitating or inhibiting infection and its therapeutic potential.