Monday, August 3, 2009

Viral Persistence

Although rather technical, this study gives a good overall look at theories
of viral persistence and with the goal of understanding basic principles in
viral pathogenesis and ...resolve persistent infections of humans. Oldstone
MBA (2009) Anatomy of Viral Persistence. PLoS Pathog 5(7): e1000523Ingredients
of a Chronic Viral Infection

The many millions of humans who have life-long virus infections represent a
major health issue for the 21st century but also a unique opportunity for
investigative virologists.

For persistent virus infections to endure, two ingredients are essential.

The first is a unique strategy of viral replication; that is, instead of
killing its host cell, the pathogen causes little to no damage so it can
continue to reside in those cells.

The second requirement for persistent virus infection is an immune response
that does not react to or remove virus-infected cells.

Overall, our knowledge of how viral genes and cellular factors interact to
allow persistence to occur is incomplete. Although our libraries contain
volumes of facts on this subject, many physiologic functions and
interrelationships of viral genes with host genes that establish persistence
remain, in large part, unknown.

We do know that acutely infected cells express viral peptides, which, when
attached to host major histocompatibility complex (MHC) molecules on their
surfaces, signal the immune system to kill such cells. However, viruses
apply numerous avoidance strategies to persist.

One is direct selective pressure to suppress the infected host's innate
and/or adoptive immune system that would otherwise destroy them (reviewed
1,2,3). For example, viruses can alter or interfere with the processing of
viral peptides by professional antigen-presenting cells, thereby restricting
expression of MHC/peptide complexes on cell surfaces, a requirement for
activation and expansion of the T cells that normally remove infected cells.


Additionally, viruses can downregulate co-stimulatory and/or MHC molecules
also required for T cell signaling and expansion; they can inhibit the
differentiation of antigen-presenting conventional dendritic cells (cDCs),
and can infect effector T and B cells directly. Similarly, to persist in
infected cells, viruses can disrupt the processing or migration of viral
peptides or viral peptide/MHC complexes to the cells' surface, thereby
removing the recognition signals for activated killer T cells.

Finally, viruses that persist frequently infect neurons, which have defects
in TAP, a molecule required for the translocation of viral peptides to
endoplasmic reticulum (ER)4,5 . Perhaps neurons can also actively prevent
cytotoxic T lymphocytes (CTLs) or natural killer (NK) cells from
degranulating and thereby limit the activity of such virus-removing effector
cells. Since neurons are essential to health but rarely regenerate when
destroyed, Darwinian selection likely caused them to evolve mechanisms to
avoid immunologic assault. Such events would allow infected neurons to
escape immune recognition and live, as well as allow viruses to persist in a
neuronal safe house...

The full study is available here:

http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000523

Other articles of similar nature that while not specifically about ME/CFS
include many of the principles of biomedical research involving ME/CFS
include:

Viral Control of Mitchondrial Apoptosis (cell death)

http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000018

Duca KA, Shapiro M, Delgado-Eckert E, Hadinoto V, Jarrah AS, et al. (2007) A
Virtual Look at Epstein–Barr Virus Infection: Biological Interpretations.
PLoS Pathog 3(10): e137. doi:10.1371/journal.ppat.0030137

http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.0030137

The possibility of using computer simulation and mathematical modeling to
gain insight into biological systems is receiving increased attention.
However, it is as yet unclear to what extent these techniques will provide
useful biological insights or even what the best approach is.

Epstein–Barr virus (EBV) provides a good candidate to address these issues.
It persistently infects most humans and is associated with several important
diseases, including cancer.

We have developed an agent-based computer model/simulation (PathSim,
Pathogen Simulation) of EBV infection. The simulation is performed on a
virtual grid that represents the anatomy where EBV infects and persists.

The simulation is presented on a computer screen in a form that resembles a
computer game. This makes it readily accessible to investigators who are not
well versed in computer technology. The simulation allows us to identify
switch points in the infection process that direct the disease course
towards the end points of persistence, clearance, or death, and identify
conditions that reproduce aspects of EBV-associated diseases.

Such simulations, combined with laboratory and clinical studies and animal
models, provide a powerful approach to investigating and controlling EBV
infection, including the design of targeted anti-viral therapies.
 
* * *
I will note that when I finally got sleeping pills that put me to sleep for 8 hours every night without fail, after a few months my immune system regenerated enough to beat back the virus, with 6 months of a 101 fever. 
 
I am still fighting off the effects of the damage caused by several years of sleeping only 2 hours a night, but I definitely feel better than I did before those sleeping pills.




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