Debunking myths on genetics and DNA

Thursday, December 15, 2011

So mice can be vaccinated against HIV. What about humans, though?


I hope I can get away with yet another paper on gene therapy this week. You may actually have already heard about this one: it came out at the end of November and it had quite some resonance because the researchers claimed to have established lasting immunogenicity to HIV in mice‚ using, again gene therapy.

I have already discussed the potential use of gene therapy to cure HIV. In fact, the only human to ever be "cured" of HIV was a leukemia patient who, after receiving a genetically modified vector, developed HIV-resistant T-cells. In that case gene therapy was the only way to save the patient's life as he was dying of leukemia. It was quite an interesting study and I loved learning about it. However, in general, gene therapy is NOT a feasible way to end the AIDS pandemic. It's too expensive, too risky, and 2/3 of the infected people live in South Africa where even drugs are too expensive, you can imagine gene therapy.

No, the most efficient means to wipe out the virus, from both an economical and a clinical perspective, is a vaccine.

Okay, I'm biased. I work on HIV vaccine design. And when this paper appeared in Nature many colleagues rolled their eyes. "Too risky." "Too impractical." "It'll never work in humans." Which meant I had to read the paper. So I did.

From the abstract:
"As an alternative to immunization, vector-mediated gene transfer could be used to engineer secretion of the existing broadly neutralizing antibodies into the circulation. Here we describe a practical implementation of this approach, which we call vectored immunoprophylaxis (VIP), which in mice induces lifelong expression of these monoclonal antibodies at high concentrations from a single intramuscular injection. This is achieved using a specialized adeno-associated virus vector optimized for the production of full-length antibody from muscle tissue. We show that humanized mice receiving VIP appear to be fully protected from HIV infection, even when challenged intravenously with very high doses of replication-competent virus. Our results suggest that successful translation of this approach to humans may produce effective prophylaxis against HIV."
So, it is some kind of vaccine. And at the same time it's not. In a standard vaccine you inject a deactivated form of the virus in order to elicit antibody production in the host. With this new method, instead, you inject a virus which carries the genes for the antibodies. Instead of letting the immune system find a way to produce the antibodies, the researchers provided the "instructions" on how to make them: they injected into the muscle a viral vector containing the genes for the antibodies.

The vector used in the study is a self-complementary adeno-associated virus, which I discussed here. The researchers produced AAV vectors that either expressed luciferase (for the controls) or the neutralizing antibody b12 and administered them to mice through a single intramuscular injection. The mice were then populated with human peripheral mononuclear cells and then challenged with HIV. After the challenge, most mice expressing luciferase showed dramatic loss of CD4 cells (the cells infected by HIV) whereas mice expressing b12 antibody showed no CD4 cell depletion. Basically, the therapy was working.

They also tested a cocktail of historically known broadly neutralizing antibodies: b12, 2G12, 4E10, and 2F5. Again, after being adoptively populated with huPBMCs, the mice were
"challenged by intravenous injection with HIV and sampled weekly to quantify CD4 cell depletion over time. Animals expressing b12 were completely protected from infection, whereas those expressing 2G12, 4E10 and 2F5 were partly protected."
Finally, they repeated the experiment with one of the newest and most potent broadly neutralizing antibodies, VRC01, and found similar results, with higher protection established at higher doses of the vector.

The fact that the mice were challenged intravenously is quite impressive because mucosa routes present a bottleneck for the virus, whereas intravenous challenges are much more efficient in initiating the infection.

A number of things remain to be seen, the safety and efficacy of the therapy in particular. In this hemophilia B study the administration of intravenous AAV showed lasting results, even though the new genes were expressed at a low level. However, other scAAV studies have failed and, as an additional word of caution, we should not forget all the therapies successfully tested in mice that later failed in humans: assuming this technique passes the required safety checks, it still remains to be seen whether results in humans would be comparable to the mouse model.

Still. Despite my original bias, I confess I find these results pretty cool. Don't tell my boss, though!

Balazs, A., Chen, J., Hong, C., Rao, D., Yang, L., & Baltimore, D. (2011). Antibody-based protection against HIV infection by vectored immunoprophylaxis Nature DOI: 10.1038/nature10660

Photo: Sunset on Croc Rock and the Rio Grande. Shutter speed 1/25, focal length 38mm, f-stop 5.0, ISO speed 100.

ResearchBlogging.org

2 comments:

  1. Fascinating things going on out there.

    ReplyDelete
  2. I agree, the idea is brilliant. It's the kind of thing that would never get to Africa, methinks, but still, a brilliant idea.

    ReplyDelete

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