HHV-6 Mediated Mitochondrial Modulation and Its Association to ME/CFS

A project summary as written by Bhupesh Prusty:

Infections are frequently associated with chronic disease development and likely, play crucial roles in
the onset or progression of several human disorders that are not classified as infectious diseases.
Myalgic encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS) is one such example. However, the
precise role of pathogens in ME/CFS development remains, predominantly, uncharacterized. Human
Herpesvirus 6 (HHV-6) is frequently associated with several human diseases including ME/CFS. Work
from my laboratory as well as from others have shown that HHV-6 frequently integrates into human
chromosomes in order to achieve latency (ciHHV-6). Originally, ciHHV-6 was thought to be the dead
end for the virus. However recent publications demonstrate that certain timely triggers like
circumstances of immune suppression or influence of various drugs and/or pathogenic infections can
activate the integrated virus.

Our preliminary work shows that HHV-6 targets the cell’s energy reserve, the mitochondria, during
both active infection and activation from latency leading to mitochondrial dysfunction, a condition that
is also frequently associated with ME/CFS. Using a unique latent and chromosomally integrated
HHV-6 cell culture model, we have observed down regulation of a small non-coding human microRNA
in response to viral infection that induces expression of tumor suppressor protein p53 and
subsequently that of Drp1 leading to mitochondrial fragmentation. Because of these events,
mitochondria from the infected cells tend to have lower ATP generation capacity and reduced
efficiency for maintaining calcium homeostasis. In this proposal, we aim to dissect out the contributing
factor from HHV-6 that is directly responsible for the signaling processes leading to host cell
mitochondrial alteration. We have identified several viral miRNAs that are specifically expressed
during both active infection and viral activation. We hypothesize that these viral miRNAs play a key
role in alteration of mitochondrial fission-fusion dynamics. Our final aim is to link HHV-6 and
mitochondrial alterations using ME/CFS patient materials. Molecular mechanisms behind direct
association between HHV-6 and human mitochondria have never been studied before. The proposed
project aims to elucidate the molecular mechanism(s) by which HHV-6 infection actuates mitochondrial
dysfunction in ME/CFS patients, likely, resulting in the development/progression of ME/CFS.

The anticipated outcome of this pioneering research idea is the elucidation of a novel infectioninduced
mechanism for the onset and/or progression of ME/CFS. Understanding etiology of
mitochondrial modulation from thus far unknown causative agents will open new targets for drug
development. Infectious agents behind mitochondrial modulation in ME/CFS are poorly characterized
and the proposed research aims to address this unexplored avenue. The idea that a common virus
like HHV-6 could associate with host cell mitochondria and modulate its function (and contribute to
disease) has not been hypothesized before. I believe that my project has tremendous potential to
revolutionize the preconceived theories about pathogenic causes behind ME/CFS and is in line with
the Solve ME/CFS Initiative’s mission as well as funding objectives.