Synthetic intra-cellular HIV vaccine

This method of HIV treatment is based on placing genes that code for synthetic antibodies against HIV into CD4 cells.

There is a part of the immune system that is inside mammalian cells called TRIM21. TRIM21 is the intracellular receptor for the Fc chain of antibodies.

A &  B - These ends bind to antigens.  C - The Fc chain. Trim21 binds to this.

A & B – These ends bind to antigens.
C – The Fc chain. Trim21 binds to this.

 

The Fc chain is the lower part, the “handle” of the antibody shown.

When Trim21 binds to an Fc chain of an antibody, whatever that antibody is attached to gets covered with ubiquitin.

proteasome

The proteasome, the garbage disposal of the cell. Proteins go in one end, and come out the other in small pieces.

 

Ubiquitin marks the material for destruction by the garbage disposal of the cell.

 

 

 

HIV Virion – Courtesy NIAID/NIH

There are a number of HIV proteins. GP120, the attachment protein of the cell. GP41, the reverse transcriptase, integrase, and Env – the envelope protein.

It is fairly straightforward to produce antibodies to these proteins. That has never been a problem. The problem has been that viral envelope, and the rapid mutation rate of the part of GP120 that is available. Antibodies can only attach to what is right there on the surface. Change the surface, and the antibody doesn’t work. And everything inside that lipid membrane is protected. So the problem has always been getting access to those proteins.

The core of this proposal is to put genes for such antibodies inside the cells that are infected with the virus. That way they can kill the viruses before they are made. This is like, instead of fighting the tank, go into the manufacturing plant where tanks are made and take all the parts away.

There is a special kind of antibody produced by camelids. Alpacas, llamas and camels have them. These antibodies have a single chain for the binding region. So they look something like this.

A and B show single chain binding region.  Most antibodies have dual chain binding regions, as shown above.

A and B show single chain binding region. Most antibodies have dual chain binding regions, as shown above.

 

The reason this is important, is that a single chain antibody gene can be easily put into a plasmid, or a virus (viruses are also delivery method for genes). It will form properly inside the cell and it will work. Dual chain, normal antibodies, can take years of work to figure out how to represent them in a single gene sequence. It isn’t very practical to do that. This way can be done in months.

So, we can put this gene into a plasmid, as shown.

Typical plasmid vector design for delivering camelid antibodies

Typical plasmid vector design for delivering camelid antibodies

 

 

 

 

 

 

We put this into a cell, and it produces antibodies.

plasmid + Ab diagram

 

 

 

 

Delivering them into cells can be done in two basic ways. By putting the plasmids into particles that are of an optimum size to be taken up by immune system cells. 2-5 microns is the best size.  Or, putting them into lentivirus particles in order to deliver them specifically to the CD4 cells will also work.

That’s the short version.

This will work. It should be the only method of treatment that can be successful after antivirus therapy fails. It could return a person to normal health, free of noticeable disease. It would need to be renewed every 18 months or so, but that is doable.

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