A brief exploration of the way some modern viruses act and ancient viruses have acted to benefit their hosts - particularly humans - today and through evolutionary history, by various means (such as targeted destruction of pathogenic bacteria and introduction of new genetic material).
2. Viruses play many roles
• Viruses are infectious particles of genes packaged in protein coats.There is no
machinery for self-reproduction within the package, so the virus must deliver
its DNA to a suitable host cell to reproduce.
• Viruses are widely known as pathogens due to the roles they can play in
various diseases.
• There are definitely plenty of pathogenic viruses.
• There are also other viruses whose relationships with humans are a bit more
complicated.
• A few examples of those kind of relationships currently identified and being
further researched:
• GBV-C: Co-infection with HIV can slow its progression
• Bacteriophages: treatment of persistent bacterial infections
• Ancestral Endogenous Retroviral DNA: Gene regulatory network in human neural progenitor cells
and Hemo
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3. GBVirus C – Potentially slows progression of HIV
into AIDS
• Single stranded positive RNA genome
• Known to infect humans, but not known to cause disease.
• Replicates primarily in lymphocytes, while HIV replicates in macrophages
(Both are different types of white blood cells in the immune system).
• Several (but not all) studies, as well as in vitro models demonstrated GBV
slowing HIV progression. Impact:
• Lower HIV-1 RNA levels
• Higher CD4 cell counts
• Slower progression to AIDS
• Improved response to HAART (Highly active antiretroviral therapy)
• Reduction of mortality and better quality of life!
• May be because of several proteins the viral NA encodes for, NS5A
phosphoprotein and E2 envelope protein.
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4. Paths to new drugs?
Proposed molecular
interactions of GB virus C with
HIVFrom Role of GB virus C in modulating HIV disease
Proposed molecular interactions of GB virus C with HIV(1)GBV-C alters
the cytokine profile during HIV -infection, thereby stabilizingTh1 cytokine
expression [127,128]. (2)A major source ofTh1 cytokines are circulating
CD80+pDCs, which are increased in GBV-C co-infection [129]. (3) HIV
replication is also inhibited by GBV-C proteins [87,132]. (4)GBV-C NS5A
phosphoprotein induces SDF-1 release, thereby decreasing CXCR4, an
important co-receptor of HIV [133–135]. (5) Furthermore, secretion of
RANTES, MIP-1α and MIP-1β – natural ligands of the other HIV co-receptor
CCR5 – is elevated duringGBV-C co-infection leading to lower surface
expression of CCR5 [131,137]. (6) Direct inhibition of HIV entry by GBV-C E2
protein has been proposed and interaction of GBV-C E2 with the HIV-1
fusion protein has been shown [141–144]. (7) Furthermore, GBV-C E2Abs
have been demonstrated to neutralize HIV-1 infection by inhibition of viral
attachment [145]. (8)GBV-C altersT-cell activation leading to a lower
percentage ofT lymphocytes expressing CD38 [147]. (9) Finally, GBV-C co-
infection leads to lower Fas expression onT and B lymphocytes, thereby
reducing Fas-mediated apoptosis [151].
Ab:Antibody; CCR: Chemokine receptor; GBV-C: GB virus C; pDC:
Plasmocytoid dendritic cell; RANTES: Regulated on activation, normalT-
cell expressed and secreted; SDF-1: Stroma- derived factor-1.
4 2/18/2018 GB virus C with HIV
5. Bacteriophages and PhageTherapy –The enemy of
my enemy is my friend
• Bacteriophages, or phages, target specific bacterium.
• Phages utilize cell machinery to produce (or interact with) lysins, enzymes that cause
the host cells to lyse open or trigger autolysis.
• Lysins or lysin coenzymes are a potential area of research for targeting antibiotics
(rather than wiping out an existing microbiome).
• The exponential reproduction of a virus that is harmless to humans but lethal to
infectious bacteria can quickly overwhelm and eliminate bacteria in harmful
infections.
• When bacterial cells lyse open, their contents are released into the area of the body they’re infecting, so an
acute immune response to “endotoxins” might make you feel terrible for a while or potentially overload the
systems of individuals with reduced ability to systemically filter and remove them.
• Area of research for treating and developing treatments for antibiotic resistant
bacterium.
• Regulatory approval in western nations? People don’t like the idea of introducing self-
replicating entities with the capability to evolve into themselves…
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7. Ancestral Endogenous Retroviral DNA
• Retroviruses tweak the central dogma of biology.They inject RNA that
modifies DNA that then transcribes the newly modified DNA to transcribe
viral RNA to continue the life cycle of the virus.
• Sometimes, there are errors in the process and the newly modified DNA
doesn’t encode for new viruses, but changes the code of the DNA in a way
that is not immediately apparent. If that DNA is or ends up in a gamete, it may
be passed on to offspring (endogenous), where over generations, through
exposure to various viruses, more endogenous DNA accumulates and
emergence of new proteins within the organisms have more profound effects.
• As this happens, generation after generation, the proteins encoded by
endogenous viral DNA modify the machinery of the cell in ways that
contribute to various fates for members of the virus host species:
• Maladaptive: reduced fitness, may not pass on heritable material
• Neutral: more likely “at the given point in time”… May eventually contribute to new proteins that
could be bad or good
• Proadaptive: Evolution of new species with increased fitness
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8. Ancestral Endogenous Retroviral DNA
• Viruses in the distant past (millions of years ago) helped contribute to human
evolution that differentiates us from our marsupial and simian cousins.
• Within the human genome:
• ~ 100,000 endogenous sequences of viral DNA
• ~ 8% of the human genome
• Several studies have made interesting connections:
• Hemo: Common to all simians
• TRIM28 network
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9. HEMO, an ancestral endogenous retroviral envelope
protein shed in the blood of pregnant women and
expressed in pluripotent stem cells and tumors
What’s it there for?
• Stretch of viral DNA discovered at Gustave Roussy cancer research institute:
• More than 100 million years old
• Produced in the placenta and early embryo
• Placentals have longer internal gestation periods
• Common to placentals, almost identical among simians.
• Consistency across species implicates important role in fetal development – adaptive function as yet
unknown!
• Knocking out the gene results in reduced viability… function is apparently important.
• Also highly transcribed in several tumors:
• Germ cell, breast, and ovarian tumors
• “Stemness” marker of normal cells and target for immunotherapeutic approaches in treating
tumors
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10. Co-repressor proteinTRIM28 controls a gene regulatory
network based on endogenous retroviruses in human
neural progenitor cells
• The embryonic development of our brains and nervous system are examples
of various sequences of endogenous retroviral DNA contributing to who we
currently are as a species.
• There are patterns of region and developmental stage specific endogenous
retroviruses linked to a transcriptional network based on ERVs:
• Almost 10,000 primarily primate specific ERVs act as a docking platform for co-repressor
proteinTRIM28
• TRIM28 protein establishes local heterochromatin and regulates expression of neighboring
genes:
• DNA folds in and stops transcribing genes
• Similar to operons
• Networked genes regulated by theTRIM28 protein transcribe protein coding transcripts
important for brain development.
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12. Conclusion
• Research teams have discovered much about the roles viruses play in their
ecosystems over time.
• There is a lot to learn about the roles of various viruses in and out of their
respective ecosystems.
• Why?
• Disease prevention and treatment
• Biotechnology applications
• Biomimicry
• Questions?
12 2/18/2018 Winter (break) is coming!
