Matt Gethers/20.380 HIV Project/Design Ideas/Seven Ideas

=Seven Ideas=

These are the 7 ideas that everyone likes and the assignments to do further research:
 * 1) Cellular Trap/Modulating Membrane Permeability (Jessie)
 * 2) Zombie HIV (Courtney)
 * 3) Induce Latency (Matt)
 * 4) Premature Viral Fusion (David)
 * 5) Anti-John (Stephanie)
 * 6) Engineered T-Cell (Rob)
 * 7) Lethal Gene (Yi)

It would be best to outline the idea, talk about what would need to be done, potential pitfalls, etc. I've written a small description of the idea as it was presented in our meeting, but feel free to modify.

Cellular Trap/Modulating Membrane Permeability
Prevent virions from escaping into extracellular environments by modulating membrane permeability.


 * 1) Vpu crucial in overcoming tetherin's hold on virus particles pmid=19244337
 * 2) Bst2 restricts viron release, downregulated by Vpu pmid=18342597

Zombie HIV
Trick HIV into thinking it's in one part of the body when it's in the other with the hopes of cultivating a non-pathogenic strain.

Brain-derived HIV-1 is unable to infect T-cells, but is BETTER at infecting macrophages. Cells are basically either good at infecting T-cells or macrophages, some can do both. Depends on which coreceptor they bind to. In short, HIV targets a combination of CCR5, CXCR4, and CD4 receptors.

The macrophage infection is due to V1,V2, V3 sequence changes in the envelope protein. Patients who get AIDS related dementia tend to release more neurotoxins from the destroyed macrophage.

I think this is a bad idea to follow. Reasons:

We don't want the cells to act like brain-HIV, because brain-HIV causes dementia! Bad idea.

Because the difference between brain-HIV and the stuff in the rest of the body is related to fusion (receptors and envelope proteins) - affecting this tends to just be mutated around by HIV. However, affecting this could be developed as part of an additional treatment with RT inhibitors, etc.

Induce Latency
Make all virus quiet and non-pathogenic.

The mechanism(s) for HIV-latency are not well-known. The two main theories are that CD4+ cells become infected with HIV and, if they survive, they progress to quiescence. This quiescent state is characterized by a down-regulation of transcription within the cell that limits the reproductive capabilities of the virus. The other mechanism is that the virus also has a tropism for naive CD4 cells which are also characterized by a down-regulation of transcription within the cell.

Latency is overcome when the T-cell in question is activated, thus up-regulating transcription within the cell and making viral transcription possible.

To induce a clinical "latency", we would have to trick T-cells into being quiescent or at least convince the integrated virus that the T-Cell is quiescent. As this stage appears to be defined by a global down-regulation of transcription, it would be hard to achieve quiescence without also causing someone to be immunocompromised.

Feelings: challenging, not well enough understood to continue

Promote fusion of viral capsules in the blood stream (or wherever) before fusion with CD4+ cells.

 * CD4/gp120 binding is necessary first step in fusion
 * One idea would be to have soluble forms of CD4 and/or the co-receptors floating around in the bloodstream to compete with receptors on T-cells for HIV binding
 * This is a really old idea, dating back to the 1980's (1)
 * Can't find anything that directly says this doesn't work, but time seems to be against this idea working
 * One article says this worked in vitro with laboratory-adapted strains, but not in vivo (2)
 * Possibly problematic is that this could actually increase fusion - study done with SIV (not sure if same mechanism) found it increased HIV infection in CD(-) cells because CD4 binding induces binding to CCR5 (3)
 * Summary: probably not good idea, also not very innovative
 * Possibly other ways of doing same thing?


 * 1) 1 pmid=3500514
 * 2) 2 pmid=9630213
 * 3) 3 pmid=10364284

Feelings:

 * old, probably won't work
 * didn't work in vivo
 * actually increased infection of CD4-
 * possibly new if we combine with coreceptor on a vesicle

Anti-John
Slow the rate of mutation of HIV so it can be managed with one drug (that targets something that is usually prone to mutation).

Feelings:
 * RNase H will need to be knocked out before we can add proofreading
 * could introduce new RT
 * could just target RNase H
 * not well exploited

Engineered T-Cell
Pimp out a T-cell so it dominates the virus.

Genes to be added

 * HIV-1 siRNAs?
 * Overexpressed protease?
 * gag-pol of another virus? (then our T-cells could produce virons which target CD4+ cells while still silencing HIV genes)

Genes to be removed

 * MHCs (avoid immunity all together, are they really necessary?)
 * T-cell receptor (don't want it to actually have immune system functions)

Papers

 * 1) SBs pmid=18667075
 * 2) Brake pmid=16959541
 * 3) Brake2 pmid=18180777
 * 4) MLV pmid=14993652

Lethal Gene
Encode a viral defense specific to HIV and place it in all human cells.

Wild Card: Utilizing the HIV Superinfection prevention mechanism
"Infect" cells with an HIV-like virus that carries the superinfection prevention mechanism to T-Cells. This will prevent infection of HIV at later times. There are instances of superinfection prevention that don't involve down-regulation of key surface proteins (Levy, 56-57, Taddeo, and Federico).

Is it OK to temporarily down-regulate CD4 expression on surface and then reverse?


 * 1) Federico pmid=8409934
 * 2) Federico2 pmid=7474070
 * 3) Nethe pmid=16107223
 * 4) Taddeo pmid=8503167
 * 5) Wildum pmid=16873261

Biblio

 * 1) Amado pmid=10331991
 * 2) Bagasra pmid=17049012
 * 3) Brooks pmid=14499116
 * 4) Brooks2 pmid=11283673
 * 5) Cann pmid=2235516
 * 6) Cheng-Mayer pmid=3258140
 * 7) Cheng-Mayer2 pmid=2191840
 * 8) Cheng-Mayer3 pmid=2813413
 * 9) Cheng-Mayer4 pmid=2152586
 * 10) Chun pmid=7489410
 * 11) Chun2 pmid=12552096
 * 12) Han pmid=17224919
 * 13) Hermankova pmid=12805437
 * 14) Jeeninga pmid=18439275
 * 15) Lassen pmid=15519278
 * 16) Li pmid=8918547
 * 17) Marcello pmid=16412247
 * 18) Williams pmid=17643313