Herpesviruses dUTPases

[Remy]

Basically this seems to go along with the model Dr Lerner proposed of abortive non permissive viral replication...I'm happy to see that his model is still being studied currently.

Full text here: http://www.mdpi.com/2076-0817/6/1/2/htm

Pathogens. 2016 Dec 28;6(1). pii: E2. doi: 10.3390/pathogens6010002.
Williams MV1,2, Cox B3, Ariza ME4,5.
Author information


Abstract

The human herpesviruses are ubiquitous viruses and have a prevalence of over 90% in the adult population. Following a primary infection they establish latency and can be reactivated over a person's lifetime. While it is well accepted that human herpesviruses are implicated in numerous diseases ranging from dermatological and autoimmune disease to cancer, the role of lytic proteins in the pathophysiology of herpesvirus-associated diseases remains largely understudies. Only recently have we begun to appreciate the importance of lytic proteins produced during reactivation of the virus, in particular the deoxyuridine triphosphate nucleotidohydrolases (dUTPase), as key modulators of the host innate and adaptive immune responses. In this review, we provide evidence from animal and human studies of the Epstein-Barr virus as a prototype, supporting the notion that herpesviruses dUTPases are a family of proteins with unique immunoregulatory functions that can alter the inflammatory microenvironment and thus exacerbate the immune pathology of herpesvirus-related diseases including myalgic encephalomyelitis/chronic fatigue syndrome, autoimmune diseases, and cancer.
KEYWORDS:

Epstein–Barr virus; Toll-like receptor 2; autoimmune diseases; cancer; deoxyuridine triphosphate nucleotidohydrolase; herpesviruses; lupus nephritis; myalgic encephalomyelitis/chronic fatigue syndrome
PMID:

28036046

DOI:

10.3390/pathogens6010002

dUTPases represent a family of metalloenzymes that catalyze the hydrolysis of dUTP to dUMP and pyrophosphate [1], thus preventing the incorporation of dUTP into DNA by DNA polymerases.

here is increasing evidence supporting the premise that EBV as well as other human herpesviruses also undergo abortive lytic replication and that viral-encoded proteins may be released from infected cells through pyroptosis, a highly inflammatory form of programmed cell death [35]. Although human and EBV dUTPases lack consensus secretory signal sequences, several studies have reported that the nuclear isoform of the human dUTPase is released from stressed cells [36,37]. A later study by Buschow et al. [38] demonstrated that the human dUTPase protein was secreted in membrane vesicles/exosomes from B cells. Interestingly, the human adenovirus type 9 E4-ORF1 encodes for an ancestral dUTPase [39] that is also targeted to membrane vesicles [40]. In line with these studies, we have demonstrated that the EBV-dUTPase is released in exosomes from B cells during abortive lytic replication of the virus [29]. Because exosomes are important in cell–cell communication, these vesicles may provide a route of transmission of EBV-dUTPase to other cells and/or sites of the body, enabling the viral dUTPase to modulate the cellular microenvironment by acting as an intercellular signaling molecule. Thus, dUTPase-containing exosomes provide a possible mechanism by which the EBV-dUTPase may contribute to the pathophysiology of EBV-related diseases [29].

Reactivation of the herpesviruses following stress has focused primarily on the dysregulation of the immune system. One area that has been overlooked, though, is whether virus proteins produced during lytic/abortive-lytic replication contribute to the decreased immune homeostasis following stress. In most cases, reactivation of these viruses may not result in productive infections but rather abortive infections, especially in the case of EBV [76,77,78]. However, even if productive replication occurs it may not result in clinical symptoms. Thus, the potential contributions of the virus to immune homeostasis in the host are “hidden”.

 

[Remy]

I'm curious if anyone has tried high dose folinic acid (25 mg dosed 3-4 times a day) for reactivated EBV?

http://www.ncf-net.org/pdf/UckunClinicalActivity.pdf

Intriguingly, EBV deoxyuridine triphosphate nucleot- idohydrolase (dUTPase), an early nonstructural EBV- encoded protein, has been shown to cause immune dysregulation and produce clinical symptoms observed in patients with CFS separate from its role in virus rep- lication and may serve as a new approach to help identify one of the etiological agents for CFS [45].