Wednesday, March 26, 2008

HIV Vaccine

Below I argue that the failure of recent HIV vaccine trials suggest that it is necessary to put even more effort into finding vaccines which will cause us to make antibodies which block HIV infection of cells, that is neutralizing antibodies. I now know more about just how frustrating this effort has been.

I am relying on a fairly recent review from 2004

My version of the story. Long long ago a monoclonal, called B12, which blocks HIV infection was discovered. It binds to the part of the HIV surface protein gp-120 which binds to CD-4. Unfortunately, other antibodies to this protein only block HIV which has been grown in standard cell line not HIV isolated from patients. The problem appears to be that the glycosylation (sugar coating) of gp-120 is different if the HIV grew in different types of cells.

Other neutralizing antibodies (X5 17b) bind to another part of gp-120 which seems to be required for HIV binding to another protein on the target cells surface either CCR5 or CXCR4. They aren't as famous as CD-4 but HIV has to bind to them. The problem is that this part of the gp-120 is only exposed after gp-120 sticks to CD-4.

There is a very strange mutant neutralizing antibody which would not normally be made in response to a vaccine so it doesn't count.

Finally there are some antibodies which bind to parts of HIV which are not conserved and so neutralize some strains of HIV but not others.

Finally the known neutralizing antibodies which block the most different strains of HIV 4F5 and 2E10 bind to a different HIV protein gp-41. They don't block binding to target cells but seem to block a later stage of infection.

For all of the broadly effective neutralizing antibodies other than B12 bind to parts of HIV which are only briefly exposed during the infection of cells. Thus they aren't made normally in HIV infected people, although they could be made in response to a vaccine in which these parts (epitopes) are exposed.

I think that it is not known why production of antibodies like B12 is so rare. One important issue is that after a B-Cell is activated, the antibody gene mutates. It is possible that there is no gene for any antibody which works like B12 in resting B-Cells and that several different mutations were required to produce B12. It is also possible that the epitope to which B12 binds is normally destroyed during antigen processing and they lucky patient had a lucky antigen presenting cell which didn't do so.

There are some avenues for research which were not discussed in the brief review and which I would like to discuss.

First, notice I was guessing about the closest analogue to B12 in resting B-cells. I think it would be interesting to clone the genes analogous to B12 from resting B-cells. For one thing, a vaccine would have to bind to their IG-d product in order to stimulate mutation to a B12 like antibody.

I think that it would be possible to come up with other candidate neutralizing monoclonal antibodies by screening for antibodies which compete with the currently known neutralizing antibodies for binding sites. Also to make modified proteins which are partly like gp-120 and gp41, screen for those which bind the known neutralizing antibodies and then select antibodies which bind to those proteins and not the others (I said select which means I am still into phage display).

That is, the next step isn't interesting until there are a fair bunch of known useful neutralizing antibodies.

OK then the problem becomes not we want to design a vaccine so that it will induce antibodies which neutralize HIV but rather we want to design a vaccine which will induce the following n antibodies. This is, it seems to me, definitely doable.

Basically to induce an antibody first an antigen has to stick to it. It is very easy to get proteins which stick to something - make antibodies. An antibody which specifically sticks to another antibody is called an anti-idiotype antibody. An anti-idiotype antibody would not work at all as a vaccine, but I'm not so sure about an anti-idiotype Fab.

Furthermore, the other aspects a protein must have to be an antigen are comprehensible. It must also bind to the receptor of a helper t-cell and it must be processed and presented by an antigen presenting cell. I think that fiddling with a protein to make it antigenic should be feasible. I think it would be done often but it hasn't been necessary.

No comments: