by Sharon J. Proctor, PhD
Photograpy by Rick Etkin

A petite woman with a pixie haircut sits with two German
shepherd–like dogs. Harry and Shasta are frustrated because she won’t let them come over and sniff me. The woman is SFU’s
Jamie Scott – PhD, MD, professor of molecular biology and
biochemistry, and medical researcher extraordinaire. Scott is a vital part of a massive international research effort aimed at stopping the spread of AIDS. Right now, she’s taking a break for an hour to discuss her research. “There’s no effective vaccine against HIV-1 and we desperately need one,” she says. HIV-1 is found all over the world and is what most HIV studies focus on. HIV-2 is found mainly in West Africa.

A vaccine is a benign version of a disease virus or bacterium – either the whole organism or part of its outer coat. (Flu vaccine is the outer coat.) When injected, your body produces antibodies against it, as if it were the live disease. Should you be exposed to the real disease, your immune system will recognize and attack the invader. Vaccines made from HIV-1, however, don’t work.

“The problem is, HIV-1 mutates too rapidly,” says Scott. “In the time it takes to make a vaccine, the original HIV-1 strain has mutated into several genetically different versions. What changes are the attachment sites on the virus that the antibodies attack. We need a different approach to vaccine production.”
She thinks she has it!

Viruses, cells, and HIV-1

Basically a virus is a few genes made of DNA or RNA, wrapped in a protein coat. To reproduce itself, it needs the genes of a higher organism. So it seeks a compatible host cell, attaches itself to the surface membrane, and injects its genes into the cell. The viral DNA merges with the cell’s DNA and takes total charge of it. Should the cell divide, the viral genes are passed to succeeding generations. Viruses can stay in host cells for years. Or they can order the host genes to make new viruses, thus killing the host cells.

HIV-1 targets the human immune system – by infecting T-cells (which regulate immune responses including antibody production) and macrophages (which attack bacteria, protozoa, and tumour cells). It enters by attaching to certain “binding sites” on the cell surface. These sites, which stick out from the surface, are part of a communication system cells use to keep in touch with each other.

Search for an HIV-1 “cure”

The AIDS virus attaches to two binding sites on the surface of T-cells and macrophages, fuses its protein coat to the cell’s membrane, and slips its DNA into the cell. Once inside, the viral genes take over the cell’s genes and proceed to evade and suppress the immune response.

“When your body is first infected by HIV-1,” explains Scott, “your immune system produces antibodies against certain sites on the virus surface. Then the virus mutates, which alters some of these sites. Your immune system soon develops antibodies against the new HIV-1 variant. When a third viral mutation appears, a third kind of antibody is produced. You eventually have multiple HIV-1 variants in your body, which can recombine genes and create even more variants. And when an antibody does suppress the virus, it works only against a few of the variants, not against all HIV-1 viruses.”

Only after years of HIV-1 infection does the body finally start producing effective antibodies that will suppress a lot of different variants. They bind to sites that the virus cannot change without harming itself. But it’s too few too late. In the end, the immune system loses too many T-cells and thus the ability to resist disease. Scientists have actually isolated four of these effective antibodies. Unlike those produced early on, they bind to sites on the virus that don’t mutate. And they seem to stop the different HIV-1 variants. The trick now is to teach the human body to make more of these antibodies.

To stop a virus, antibodies (which are proteins) only need to attack small bits of the viral protein coat. Jamie Scott’s focus is the non-mutating regions of the HIV-1 coat. Years ago she had assembled a “library” of hundreds of millions of short protein fragments, called peptides. She exposed these peptides to the four effective anti-HIV-1 antibodies, to see what would happen. Indeed, the antibodies bound to certain peptides as if they were part of the HIV-1 coat. Her goal is to create a vaccine with these peptides, one that will cause the immune system to produce antibodies that attack only non-mutating virus sites – and thus prevent HIV infection.

However, there’s still a major problem. Scott explains: “The four human antibodies that successfully bind to HIV-1 viruses don’t appear until months or years after initial exposure to HIV-1. Not only that, they have an unusual protein structure. This structure may be related to the changes in antibody genes caused by all the HIV-1 mutations. The question is, how necessary is this altered structure for neutralizing the different HIV-1 strains?”

She’s examining antibodies produced at different times after
HIV-1 infection to see when the structural changes occur, how the process is controlled, and if effective antibodies with more normal structures are present early on (even in tiny amounts). “It would be best if the vaccine didn’t have to produce antibodies with an unusual structure. On the other hand, the antibodies need to bind to hard-to-get-at sites on the virus. Can typical antibodies do this? We need the answer in order to make the right vaccine.”

Scott describes her other HIV-1 projects, her work with SARS, and collaborations with laboratories all over the world. All too soon, though, the hour is up. Suddenly, two dogs lunge and begin eagerly sniffing my outstretched hands. aq

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