By David N. Leff

Eight rhesus monkeys (Macaca imulatta), immunized with a novel vaccine, are alive and healthy some five months after being shot full of deadly immunodeficiency virus, which killed four of eight unvaccinated monkeys. Science, in its current issue, dated Oct. 20, 2000, documents their survival in a paper titled: "Control of viremia and prevention of clinical AIDS in rhesus monkeys by cytokine-augmented DNA vaccination."

The article's senior author is virologist-immunologist Norman Letvin, chief of viral pathogenesis at Harvard-affiliated Beth Israel Deaconess Medical Center in Boston.

"The approach we've taken," Letvin told BioWorld Today, "is to use a vaccine strategy that will generate high levels of virus-specific cytotoxic T lymphocytes. These," he explained, "are AIDS virus-directed killer T cells that recognize cells infected with HIV, and eliminate them from the body.

"A number of such prototype strategies are currently being explored," he went on. "In this study we report one of a number of potential strategies that in our hands - at least in the monkey AIDS model - generated relatively high levels of this immune response. The unique aspect of this approach is that we tried to harness a vaccine technology specifically designed to make these kinds of immune T cells, then looked at the consequences for infection and disease evolution in monkeys that we vaccinated before they were exposed to the virus.

"Some monkeys," he recounted, "we optimally vaccinated. A control group, not. Those sham-vaccinated animals, after being challenged with virulent AIDS virus, developed high levels of virus replication in their blood. They lost their helper CD4-positive T lymphocytes, and went on to develop immunodeficiency and death.

"While optimally vaccinated animals did become infected after exposure to the virus," Letvin went on, "the level of virus that replicated in their blood was quite low. These monkeys never lost their CD4 T cells in the circulation, never developed immunodeficiency, and remain alive and healthy."

Vaccine Mixes Simian, Human Viral Targets

"In order to generate this killer T-cell response," Letvin continued, "you need to have active synthesis of viral protein going on in host cells. So there are a couple of different approaches to doing this relatively safely. One is naked DNA; the other live recombinant viral vectors. We chose a naked DNA plasmid - a circular piece of the AIDS viral gene, which stimulates the immune system to make those killer T cells. However, the other approach would probably have worked as well."

The Beth Israel-led method did not involve aiming its vaccine payload specifically at the virus-targeted T cells. "Therefore," Letvin pointed out, "we gave a very large inoculum of the naked DNA, which presumably got into an adequate number of the cells that it needs to get into. But," he added, "this technology has been far from optimized to date. I'm sure there will be better ways of doing it than what we've done here."

What he and his co-authors did was construct a multi-threat anti-AIDS vaccine that aims to cut off the virus at every one of its passes. The team's naked DNA ingredient combined viral proteins from both simian and human immunodeficiency viruses - SIV and HIV. To beef up these immune system bulls' eyes, they patched in a potent adjuvant - lymphocyte growth factor, the interleukin-2 cytokine - generated by the host's immune defenses. The co-authors saw and raised this lymphocyte-boosting protein by enhancing the vaccine with direct aliquots of the protein itself or DNA plasmids containing genes expressing it.

"A DNA plasmid is easier to make and transport than a protein," Letvin pointed out, "and it can be given only once. The protein is quickly cleared by the body, and must be administered many times to maintain a therapeutic level. Its gene, by contrast, multiplies and expresses the protein continually."

He made the point, "In vaccine development, economy and ease of delivery are critical factors. The ultimate test will be how widely and efficiently the vaccine can be administered in undeveloped or remote areas of the world. There are large parts of Africa, for example, where HIV is absolutely endemic. Huge percentages of the population - as many as 50 percent - are infected with HIV. For such populations," he observed, "the HAART therapy - highly active antiretroviral protease treatment - is too expensive. So a vaccine such as we report in Science could be a viable option for people infected with HIV - and crucial for curbing the pandemic in those parts of the world."

In 1999, the United Nations Program on AIDS estimated that 5.4 million people were newly infected with HIV, and about 2.8 million died of AIDS.

'Numbers Of Approaches' Await Human Trials

As regards human trials of his vaccine, Letvin is of the opinion that "there are a number of types of approaches that should be able to generate the same type of killer T-cell response. There is every reason to hope that some of these might work well in humans. These kinds of vaccines will be going into testing in the very near future. Some are already in human trials, and hopefully it will be only a couple of years before we have a sense as to whether these observations in monkeys will translate into similar findings in people."

So far, the vaccine, as a proof of principle, has been given only to the AIDS-modeling monkeys as pre-infection, preventive immunization. Whether it could also benefit people already HIV positive, Letvin said, "would have to be studied. We have no evidence one way or the other. Conceptually," he added, "I would have no problem either way."

He and his co-authors will be testing not only the vaccine reported in Science, but "a large number of other approaches as well. I see this as a conceptual piece of work," he said, adding, "We're not particularly tied to this particular vaccine. Rather we're tied to the idea of making a killer T-cell response through vaccinations."

Beth Israel, he noted is applying for patents on his group's discoveries. "But patents on all of these," Letvin observed, "remain extremely complex. A lot of people have a piece of a lot of this. Luckily, I'm in an academic setting," he concluded, "and therefore can just do experiments, while letting others worry about that intellectual property."

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