Designer immunity, vectored immunoprophylaxis and the future of medicine

Antibody Molecule
Antibody Molecule (Photo credit: sc63)

 

One of my very favorite aspects of being a scientist is being right on the cutting edge of modern research. I have the pleasure of working in an environment where new discoveries are made daily that span from the mundane to the revelatory. Today I want to take the time to write about a recent paper that for me came to my attention that falls solidly in the revelatory category.

 

 

This 2012 Nature paper by Balazs et al is a great example of modern virology in combination with immunology is being used in novel ways to combat different health issues. Read on to see how this group used a viral vector to give mice protective immunity against HIV infection.The title of today’s paper is “Antibody-based protection against HIV infection by vectored immunoprophylaxis” and was published in the January 2012 volume of Nature. Essentially, this group made mice resistant to a subsequent HIV challenge by having them produce very strong anti-HIV antibodies. They got the mice to produce these antibodies by way of a viral vector containing the sequence for a broadly-neutralizing HIV antibody known as b12. These recently discovered antibodies are very special, as they are the most effective at neutralizing many different types of HIV. In humans these antibodies begin to arise after extensive affinity maturation to HIV as HIV can mutate quickly and evade all but the most broadly acting antibodies with relative ease. This rapid rate of mutation and evasion of immune control is a huge hurdle in developing effective vaccines or antivirals to HIV; once a vaccine or antiviral is on the market it will select for the spread of resistant strains until the vaccine or antiviral is no longer effective on the remaining population. We have seen this time and again with the introduction of new antivirals so that now many different compounds are used together in what is known as HAART, or highly-active antiretroviral therapy.

So now that we know what is responsible for the immunity (broadly-neutralizing antibodies) how exactly did they get the mice to express them? This is where the viral vector comes in. In this study they use adeno-associated virus 8 (AAV8) as their vector. This is a really good choice because AAV does not cause disease in people, it doesn’t provoke a significant immune response, and it isn’t fully replication competent on its own. When AAV infects the host cell it integrates with host DNA in such a way so that the CMV promoter engineered in by the researchers drives the expression of the antibody. These antibodies are secreted into the extracellular milieu and eventually to the bloodstream where they can neutralize HIV and prevent the loss of the all-important CD4+ T cell. In this study they also used a vector with luciferase so that they could image where the virus was integrating and producing antibody in the experimental mice (see figure 1 below, Balazs et al). What they showed is that muscle tissues at the injection site are infected with the vector (1a) and begin to produce measurable amounts of antibody within a few weeks and that this antibody was stably produced for the full 52 weeks of the study in different genetic backgrounds (1B).

“a, Xenogen imaging of a representative Rag2/γc mouse 15 weeks after intramuscular injection of 1 × 1010 genome copies of AAV2/8 expressing luciferase. b, Quantification of human IgG by ELISA after intramuscular injection of 1 × 1011 genome copies of the optimized expression vector producing b12-IgG in either immunodeficient NOD/SCID/γc (NSG) and Rag2/γc (Rag2) or immunocompetent C57BL/6 (B6) and Balb/C mice (plot shows mean and standard error, n = 4). c, Concentration of human IgG in circulation as measured by ELISA on serum samples taken 6 weeks after intramuscular injection of vector expressing either luciferase or b12-IgG (ND, not detected). d, Depletion of CD4 T cells in humanized mice after intraperitoneal challenge with 10 ng p24 NL4-3 into animals that received AAV2/8 vectors expressing luciferase (left) or b12-IgG1 (right) 6 weeks earlier (n = 6).” quoted from article

 

 

 

These mice expressing the b12 antibody were then challenged 6 weeks after receiving AAV with HIV and their CD4+ cell counts examined over time (1d). I should take a moment to mention that these are humanized mice, which means that their native immune systems have been artificially reconstructed with human CD4+ cells. This can be done because the researchers used NSG mice (NOD scid gamma) which are a highly inbred immunodeficient strain and amenable to immune reconstitution with a wide variety of different human cells. While this is a huge departure from the murine immune system it does give us a look into how HIV impacts these human CD4+ cells in a living system without using humans.

When these reconstituted mice were infected with increasing levels of HIV only those actively expressing the b12 antibody kept their CD4 cells, those expressing only luciferase showed a significant drop in this cell population (see figure 3, Balazs et al). In this figure mice expressing either b12 (right column) or a the control luciferase (left column) were dosed with increasing levels of HIV and their CD4+ cell counts measured. Even at high challenge doses the b12 expressing mice all have measurable amount of CD4+ cells, indicating some level of protection.

“CD4 cell depletion in huPBMC-NSG humanized mice as a result of intravenous challenge with the dose of NL4-3 indicated on the far right. Mice expressing luciferase (left plots) were susceptible to CD4 cell loss, whereas those expressing b12 (right plots) demonstrated protection from HIV at all doses (n = 8).” quoted from article

 

 

 

What this means is that this group was capable of preventing HIV induced CD4+ cell loss in mice using a novel vectored antibody in a prophylactic manner. In humans this would be equivalent to preventing the development HIV infection and is an impressive example of the powers of modern virology coupled with immunology.

The authors go on to that that vectored immunoprophylaxis is an achievable goal for human medicine with implications ranging far outside of just infectious disease. This is a very promising science in its infancy and it will be fascinating to see what it grows into over time.

Article Citation:

1.           Balazs, A. B. et al. Antibody-based protection against HIV infection by vectored immunoprophylaxis. Nature 481, 81–4 (2012).

 

 

 

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