A Vaccine Factory Inside Each Cell

By Jason Socrates Bardi

When Edward Jenner fired his magic bullet into the arm of eight year-old James Phipps, it kept traveling. Inoculation, a new paradigm for controlling diseases, had arrived. He had lifted a cowpox scab from the hand of milkmaid Sarah Nemes to see if it would protect the Phipps boy against smallpox. It worked. And in the 200 years since, nothing has been as effective at combating, controlling, and in some cases eradicating infectious diseases as vaccines.

Smallpox, tetanus, measles, polio, diphtheria, pertussis, and several other once pandemic viral and bacterial pathogens are now gone or all but eliminated—destroyed through widespread application of Jenner’s basic technique of stimulated immune response. Inoculations have become widespread—in some cases universal. It’s no secret that vaccines are the best way to treat many epidemics.

And it’s certainly no secret for Bruce Torbett, associate professor of molecular medicine, who says his scientific outlook is deeply influenced by his background in public health. Trained in epidemiology, Torbett has seen first-hand how successful vaccines can be, and he regards vaccines as the logical approach to controlling those epidemics that rage in our society today—AIDS and cancer.

Only, the “vaccines” on which he is working aren’t really vaccines at all.

At least, they’re not vaccines in the sense of being shots that challenge the immune system to produce specific antibodies against something bad or foreign—such as an HIV virion or a cancer cell—and target it for destruction. His vaccines work by changing genotypes that make cells susceptible in the first place.

Torbett’s laboratory is developing and testing a gene delivery technique that may someday be used to deliver genes into cells, providing a high level of protection against HIV or cancer. The technique involves treating hematopoietic stem cells (HSC). These are the pluripotent granddaddy of all blood cells, located in the bone marrow, that develop into lymphocytes, platelets, erythrocytes, and red blood cells.

The basic idea is to give these cells genes that will allow them to resist an HIV infection, then implant them into tissue where they can freely grow, develop, and resist HIV infection. The same approach may be used to inhibit cells from becoming cancerous.

"I view [the therapy] as a general vaccine—something that provides protection for particular cells," says Torbett.

"Protection is prevention," he adds. "And prevention is the best form of disease control."

Take Them Out, Change Them, and Put Them Back

Several years ago, researchers noticed that against the apparent odds, some people who had had unprotected sex or shared needles on numerous occasions with multiple HIV-positive partners continued to test negative for the virus. Somehow, despite repeated high-risk exposures, they had remained uninfected.

Even more stunning was the result that cells isolated from these individuals were resistant to HIV in vitro, even though the cells had normal expression of the CD4 surface receptor that HIV envelope glycoproteins bind to and use to gain entry.

It turned out that HIV virions require a coreceptor for entry into a cell—the chemokine receptors CCR5 and, to some extent, CXCR4, present on the cell surface. Individuals who are homozygous for a mutation that knocks out the CCR5 receptor are highly resistant to infection with HIV, and individuals who are heterozygous for this mutation produce less CCR5 and tend to be among the more healthy people with HIV—the so-called "slow progressors."

Because the mutation confers some level of resistance from initial infection, provides a better prognosis for the course of their infection, and has no otherwise ill effect, Torbett felt that the coreceptor would make a good candidate for a gene therapy vaccine approach.

To do this he enlisted Carlos Barbas's support. Barbas has experience producing specific immunoglobulins, or antibodies, which are normally released into the bloodstream by B-cells to target antigens during an adaptive immune response.

Barbas and his group isolated an antibody, and its gene, that is specific for CCR5 and then designed a peptide "anchor" on one end that keeps it retained in the endoplasmic reticulum in the cell. These intracellular antibodies have been termed "intrabodies." Once the intrabody gene was incorporated in a cell, the cell would express the intrabody that would then grab the CCR5 and keep it from getting to the surface of the cell.

Thus, the cells would then be protected from infection.

This sort of therapy could prove useful as a way of treating people who are already infected with HIV. Torbett and Barbas would like to be able to deliver it into patients’ stem cells,"

However, the trick is to effectively "deliver" the intrabody genes, or for that matter any therapeutic gene, into stem or selected cells. For this approach Torbett has been working with the very virus that causes the disease—HIV.

Using a crippled version of HIV as a gene delivery vector/vehicle that can no longer spread in human cells and cause disease, Torbett’s group has shown that human stem cells can be given the gene for green fluorescent protein from jelly fish, and all cells developed from these stem cells express this protein.

"Our first generation gene delivery vectors were useful for proof of concept to get a gene into stem cells and show that it made a product, but we are now developing newer generation gene delivery vectors," says Torbett. The newer vectors may be useful for targeting stem and other selected cell populations.

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Bruce Torbett is developing and testing a gene delivery technique that may someday be used to deliver genes into cells, providing a high level of protection against HIV or cancer.