"Viral hijacking of cellular metabolism"

Steven Avery

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Viral hijacking of cellular metabolism - July 18, 2019
Shivani K. Thaker,
James Ch’ng &
Heather R. Christofk

This review discusses the current state of the viral metabolism field and gaps in knowledge that will be important for future studies to investigate. We discuss metabolic rewiring caused by viruses, the influence of oncogenic viruses on host cell metabolism, and the use of viruses as guides to identify critical metabolic nodes for cancer anabolism. We also discuss the need for more mechanistic studies identifying viral proteins responsible for metabolic hijacking and for in vivo studies of viral-induced metabolic rewiring. Improved technologies for detailed metabolic measurements and genetic manipulation will lead to important discoveries over the next decade.

Although it’s been known for over half a century that viral infection alters host cell metabolism, the mechanisms and consequences of virus-induced metabolic reprogramming have only begun to be studied in detail over the past decade (Fig. 1). Viruses clearly rely on host cell machinery to propagate—they promote anabolism for generation of macromolecules needed for virion replication and assembly ... we point out gaps in knowledge and important unknowns in the viral metabolism field that will hopefully be elucidated in future studies.

Virus infection induces metabolic reprogramming in host cells

In this section, we describe what is currently known about how different viruses rewire host cell metabolism to facilitate optimal viral replication. ... the precise metabolic changes induced by specific viruses are often context-dependent and can vary even within the same family of viruses or depend on the host cell type that is infected. While improved technologies have enabled a more in-depth analysis of how different viruses alter host cell metabolism to promote virus replication, future studies are needed to further uncover mechanisms involved in viral metabolic reprogramming.

SA: So far, virus replication by hijacking the host cell replication is simply assumed.

Adenovirus is a double-stranded DNA virus that relies entirely on host cell machinery for replication [9].

.... Pharmacologic inhibition of GLS by CB-839 reduces optimal replication of not only adenovirus, but also diverse viruses including HSV-1 and influenza A virus [12].

Herpes family (HSV-1, HCMV)
Herpesviruses are DNA viruses that undergo both lytic and latent phases of their viral reproduction cycle. While there are more than 100 known herpesviruses, about eight are known to infect human cells exclusively, and can lead to latent infection in specific human tissues [13].

Herpes simplex virus 1 and 2
Herpes simplex virus 1 and 2 (HSV-1 and HSV-2) are common viruses that typically cause cold sores and genital herpes, respectively. After entry into the host, both viruses replicate in epithelial cells before ascending into the neural ganglia where latent infection is established [13]. ,,, deficiency of the lncRNA decreases viral replication of HSV-1, vaccinia virus, and vesicular stomatitis virus [17]

... It has been hypothesized that HSV-1 has evolved to promote nucleotide biosynthesis in host cells since the virus infects and replicates in non-proliferative cell types such as neurons. ... 2-DG treatment has also been shown to attenuate HSV-1 replication [23, 24],

Vaccinia virus
Vaccinia virus (VACV) is a large, enveloped DNA virus and member of the poxvirus family, which includes the variola virus that causes smallpox. VACV is unique in that it replicates in the cytoplasm of the host cell instead of the nucleus like most DNA viruses [46].

Limitations of current studies and future directions
... Additionally, it is intriguing that infection by the same virus can have contrasting effects on different types of host cells, as is the case in ZIKV-infected human versus mosquito cells.
A major limitation in our current understanding of viral-induced metabolic reprogramming stems from the fact that most of the work characterizing viral alterations to host cell metabolism so far has been carried out in vitro. However, metabolism in vivo is known to be quite different from that found in vitro in cell culture conditions. In vivo models to assess metabolic changes induced by virus infection are needed to have a more accurate understanding of viral metabolism and facilitate therapeutic antiviral strategies.

Additionally, many viruses, including HSV-1 and HCMV, undergo both lytic and latent phases of infection in host cells, but most studies characterizing metabolism by both viruses have focused only on the lytic phase. Determining whether metabolic changes are unique at different phases of infection would be of interest.

... Whether or not an individual’s diet may also impact virus replication would be an interesting area for further investigation.

Influence of oncogenic viruses on host cell metabolism

Nearly 10% of all new cancer cases worldwide are attributable to oncogenic viruses. These viruses include human papillomavirus (HPV), hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein-Barr virus (EBV), Kaposi’s sarcoma-associated herpesvirus (KSHV), and human T-cell lymphotropic virus type 1 (HTLV-1) (Fig. 3) [58]

Conclusions and future directions
While many studies have demonstrated that viruses reprogram cell metabolism and rely on metabolic changes for optimal virus replication in vitro, significant work remains to determine mechanistically what viral proteins interact with host cell machinery to induce such alterations and characterize whether the same metabolic perturbations occur during infection in vivo. ... The future is certainly ripe for discovery in the viral metabolism field.
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