Matt Gethers/20.380 HIV Project/Design Ideas/Brainstorm
Design Ideas Brainstorm
Some Design Constraints/Observations/Questions
- Viral load doesn't necessarily correlate with pathology. There are examples of Lentiviruses that exist at high viral titer in the host without any adverse effects Badley (pg. 5, end of 3rd graph). It may be worthwhile to decouple the problems of eliminating the virus entirely and just getting it to play nicely with the host. Given less pathogenic strains some sort of competitive advantage could do the trick.
- Therapies that depend on the virus remaining the same (not mutating) will fail unless they can clear out the viral population on a time scale faster than evolution.
- Current therapies can already reduce viral loads to < 50 units RNA/ml. Our therapy would have to offer something new (i.e. achieve this same level of RNA with fewer doses or completely eradicate the viral population - including latent proviruses).
- Are there certain parts of the viral genome that HIV simply can't mutate if it's to survive?
- Why don't natural antiviral mechanisms work? Do human cells use endo and exonucleases to combat viral infections?
- Is there any way to produce aptamers in vivo?
Both naturally and medically, we seek to kill off virus. The problem with killing off something that renews itself and changes rapidly is that you will always have some sort of selection. In this case, you're selecting for more virulent strains. Rather than fighting or attempting to circumvent selection, we could use it to our advantage. The HIV strain UC1 is relatively non-cytopathic, replicates to high titer without disturbing the expression or intensity of the CD4 molecular cell surface (Levy, pg 96). If we could design an in vivo selection to drive towards this UC1 strain or something like it, we could eliminate AIDs if not HIV.
Potential Drawbacks: Hard to control selective conditions in vivo.
The idea would be to introduce some nanoparticle or vesicle expressing CD4 and chemokine receptors so as to draw virions away from human cells. Could/should engineer the CD4 and chemokine receptors on these decoys to bind virons preferentially to human receptors.
Potential Advantages: Lipids/nanoparticles are abundant. Protein engineering (especially combinatorial techniques) is far enough along where finding proteins that bind virions better than human proteins.
Potential Drawbacks: Still doesn't overcome the selection problem - the small population of virus that binds human cells preferentially will eventually become dominant.
The idea would be to make the virus's exit from its cellular host impossible. Is there a chemical that could be introduced to the bloodstream that alters membranes in this way (or some other mechanism)?
Retroviral transcription is strongly affected by the context of integration (Badley, pg 136-139). If we could introduce exogenous DNA to cell nuclei containing sequences favored by viral integration machinery, perhaps you could avoid having the virus integrate into the human genome. This Decoy DNA would be transcriptionally "dumb" so as not to produce any virus. This is more of a vaccine.
Potential Drawbacks: While we're not directly modifying the human genome, this approach probably falls under the umbrella of genetic engineering. There is also the question of delivering maintaining this exogeneous DNA in human cells.
Are any of the steps in viral integration and expression reversible? If these steps could be modeled as being in some equilibrium, then maybe you could shift the equilibrium to a state the produces less virus.
Could you surgically implant some sort of viral trap in the thymus? If you could protect the thymus from the viral onslaught, perhaps you could stabilize the immune system.
Potential Advantages: Would be a one time treatment.
Potential Drawbacks: It is a surgical procedure - doubtable as to whether it could be done in all parts of the world. There's also the problem that people in advanced stages of AIDs will already be immuno-compromised, so a surgery would be very risky.
Resonance Mediated Destruction
The idea would be to introduce Gold (or some cheaper/more abundant nanoparticle) that can act as an antenna to channel thermal energy (Schifferly). These particles would bind to virions and then a radio frequency would be applied in the vicinity of the person. Through inductive coupling, the antenna would transfer heat to the virion, eventually destroying it.
Potential Drawbacks: Would still need to find specific site on virion to bind to. Nanoparticles could be very expensive.
Certain viral proteins prevent superinfection of human cells. If we could go in the opposite direction and actually make infection a cooperative process (infection of a cell makes it more likely to be infected), perhaps you could both spare some healthy cells and cause the virus to replicate in suboptimal conditions.
Very abstract: If we had some sort of therapeutic that could change with the virus, then it wouldn't evolve beyond the medicine's grasp. The virus would essentially choose its own means of destruction. Another way of looking at it is that the medicine's renewal ability is tied to it's potency against HIV. Med would have to renew itself periodically. Predatory-Prey paper may be relevant (Balagadde).
Introducing a competitive Virus
Maybe we could force HIV to compete into extinction. If, post-infection, we could introduce a harmless virus (perhaps a modified version of the UC1 strain of HIV) that could compete with HIV for cellular real-estate, and then "rig the competition" in favor of the harmless virus, we could mediate the competitive extinction of HIV. Predator-Prey System may be relevant (Balagadde).
Potential Advantages: By using another virus as the therapeutic, we should theoretically need only one dose.
Potential Drawbacks: We are infecting someone with another virus.
Modulate Membrane Permeability
Membrane permeability changes resulting from HIV infection (Levy pg 81). Perhaps you could use this same tactic (either through lentiviral vector or chemical) to make cells impermeable to metabolites specific to viral replication or make the fusing process impossible.
Superantigens - something about the virus being able to attach to nonvariable regions of CD4 antigens (Levy pg 85). Two points:
- Could you use the same principle in finding targets for binding of small molecules (non-variable regions in gp120, etc.)
- Rather than trying to find/engineer something that binds the virus, what about producing something that the virus likes to bind to?
Picasso vs. HIV
"In general, brain-derived isolates [of HIV], although growing to high titer in CD4+ lymphocytes, are not cytopathic for these cells and do not down-regulate the CD4 protein on the cell surface" (Levy pg 109). If we could "confuse" HIV into evolving strains for particular parts of the body in the wrong parts of the body, we might be able to avoid AIDs.
Potential Drawbacks: Again, in vivo selections are difficult.
Induction of Latency
Could we cause the virus to become permanently latent? If so, it would just live quietly in the host.
Premature Viral Fusion
Could we trick the virion into releasing its RNA into the extracellular environment before fusing?
Reduce mutation rate
Could you increase the fidelity of viral replication? If so, we could have a less complicated problem to deal with.
Add an unchanging epitope to viral surface proteins.
Knock Out CCR5
CCR5-Delta32 mutation conveys HIV resistance.
Introduce Lethal Gene Regulated by HIV Presence
Introduction could be regulated by RNA Hairpin/presence of RT/presence of protease. Could be used to kill a cell when infected. If added to the genome, it could be a "vaccine."
Error fetching PMID 3258140:
Error fetching PMID 2191840:
Error fetching PMID 2813413:
Error fetching PMID 2152586:
Error fetching PMID 11805829:
- Badley, Andrew D. Cell Death During HIV Infection, Boca Raton : CRC/Taylor & Francis, 2006.
- Error fetching PMID 18414488:
- Error fetching PMID 3258140:
- Error fetching PMID 2191840:
- Error fetching PMID 2813413:
- Error fetching PMID 2152586:
- Levy, Jay A. HIV and the Pathogenesis of AIDS, Washington, D.C. : ASM Press, c1994.
- Error fetching PMID 11805829: