Here and Now | by Angela Spivey -- Endeavors, Winter 2000

Even when AIDS isn't making headlines, it ticks like a bomb.

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Alphavax
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Here and Now
by Angela Spivey

In 1992, after using IV drugs for 30 years, Clay had come to Chapel Hill to “get clean” in a rehabilitation program. During a preliminary physical exam, he was diagnosed with HIV.

His first thought was, “Since I’m going to die anyway, I might as well just keep shooting up. But then, all of a sudden, I didn’t want to be high anymore, and I wanted to live. I did not want to die a drug addict. That’s not what I am. That’s not what anybody is, really.”

Today, Clay works part-time as a peer counselor in Carolina’s Infectious Diseases clinic. He has a smile for anyone who walks into the place. But he’s also a straight-talking confidant—like your one friend who doesn’t hesitate to tell you when you’ve messed up.

“Patients are not always going to be honest with the doctor,” he says. “But they’ve got to be honest with me, because they know that I know. I come from the same place.”

He feels he does his best work at the clinic when he’s counseling patients who have returned to using drugs and are not taking care of themselves. “Because I am not a doctor, and I’m not a social worker, I’m not bound by any of the things that most of the people in the clinic are bound by,” he says. “I can just go to a client and say, hey man, get your stuff together. You’re dying.” He’ll also often put patients in touch with rehab programs, or share his experience with side effects from his anti-HIV regimen—45 pills a day.

“I just use myself as an example to let people know that there is some hope,” he says. “In seven years’ time, I’ve gained 50 pounds, I’ve gotten two jobs, gotten married. I’ve done all the things that people with AIDS think that they can’t do. Just because you’re diagnosed with HIV doesn’t mean that you’ve got to go somewhere and lay down and wait to die.”

But for Clay and other patients, the disease won’t go away. It is always there, ticking inside them. Scientists hear the ticking, too. They know that HIV is not a disease of the past. It is not a disease for someone else, somewhere else. It is a disease of here and now.

Charles van der Horst still feels a sense of urgency when it comes to HIV. It shows in the quickness of his step, a subtle glance at his watch if a visitor stays too long. And in his words. As the medical director of Carolina’s AIDS Clinical Trials Unit, van der Horst quietly tells you that he sees the AIDS clinic here grow by about 100 patients each year. In 1997, he says, 50 percent of the AIDS cases in the United States were in the Southeast.

HIV hasn't gotten much press lately. The last “big story,” it seems, were the drug cocktails—combinations of three different classes of drugs that can reduce the virus to undetectable levels. The cocktails are helping patients stay healthier and live longer. But though AIDS deaths have declined, the number of new HIV infections has remained stable. In North Carolina alone, in 1998 there were more than 1,000 reported new infections, according to the Centers for Disease Control and Prevention.

Some researchers put their hopes on vaccines. Bob Johnston, professor of microbiology, says, “A vaccine is the only way we’re going to control this epidemic.” Johnston, who is leading one effort to develop a vaccine, describes the work as “exciting and scary and hopeful all at the same time.”

Johnston’s vaccine uses a “delivery system” made out of another virus, VEE. The researchers have removed part of VEE’s genes, so it can’t spread. It’s used as a vector—a carrier that delivers parts of a pathogen to the body. VEE is a good carrier because it naturally goes straight to the lymph nodes, which are “the heart of the immune system,” says Nancy Davis, research associate professor of microbiology. The VEE vector has been effective in delivering many different types of genetic material. “We think that’s the power of it—it’s kind of an all-purpose generic vector system,” Davis says.

To vaccinate against AIDS, the VEE will deliver partial genetic material of HIV. Since it’s only part of a virus, the HIV isn’t infectious, but once inside the body, it will produce proteins that will provoke an immune response. The researchers have tested this system in monkeys using SIV, the simian immunodeficiency virus. They vaccinated the animals, then infected them with a large amount of SIV. The vaccinated monkeys have remained disease-free for a year and a half, and one of them has a level of virus that is too low to detect. Half of the unvaccinated control animals, however, died within three months from SIV.

Johnston’s team received a $12 million grant last fall from the National Institute of Allergy and Infectious Diseases to perfect the vaccine. This team includes Davis; Ron Swanstrom, professor of biochemistry; Jeffrey Frelinger, professor and chair of microbiology; Phil Johnson of Ohio State University; and David Montefiori of Duke University. Their work includes manipulating the gene sequences of the VEE vector and the partial HIV so that the vaccine will elicit a stronger immune response, Davis says. They’ll tweak the VEE vector, for instance, so that it will target not just the lymph nodes, but specific cells in the nodes.

A related group is working on a more immediate solution—designing a first-generation vaccine based on the monkey results. AlphaVax, Inc., a company based on the VEE delivery system and founded by Johnston, Davis, and Jonathan Smith of the United States Army Medical Research Institute of Infectious Diseases, has received funding for this version of the vaccine from the International AIDS Vaccine Initiative. The vaccine will be targeted toward a strain of HIV common in South Africa and should be ready for human testing there by the end of 2000. With help from South African scientists, they’ll test the vaccine’s safety and track immune responses by measuring antibodies. This vaccine is “our best guess right now,” Johnston says. “It’s not very likely that our first attempt will work. But we’re in this for the long haul.”

Many other Carolina researchers are studying prevention in southern Africa, where almost 30 million people are estimated to be infected with HIV. “AIDS is a global epidemic,” says Myron Cohen, professor of medicine. “It’s our responsibility to try to relieve it.” And because of the large numbers of people in southern Africa who are HIV positive, “We can answer questions very quickly there that we’d never be able to answer in the United States,” Cohen says.

Irving Hoffman, director of international affairs for the Division of Infectious Diseases, is leading a study in Malawi, Africa, to test a gel form of Nonoxynol-9—used as a spermicide in the U.S.—as an inexpensive, woman-controlled way to prevent HIV transmission. Nonoxynol-9 has been shown to kill HIV in test tubes. And a woman could use it without any assistance from her sexual partner. For many Malawian women, asking their partners to wear condoms is not an option. “In Malawi, it’s not a woman’s place to initiate sex—or to try to direct how it’s going to be done,” Hoffman says.

A previous study suggested that Nonoxynol-9 had no effect on HIV transmission. But, Hoffman says, most of these study participants used condoms, and the nonoxynol-9 was used as a film and didn’t dissolve properly. Hoffman’s team is recruiting 1,500 women, who will get counseling about using condoms. Only those who still say they can’t or won’t use condoms more than 50 percent of the time will complete the study. If the gel proves effective in reducing HIV transmission from men to women, it will be marketed as a method of reducing HIV risk.

Other researchers are looking for therapies for those already infected. “A lot of good things have come out of these drug cocktails,” says Joe Eron, co-principal investigator in Carolina’s clinical trials unit. The cocktails can reduce viral load—the level of HIV in the body—so that it’s undetectable. When this happens, patients’ T-cell counts—the number of immune system cells—return almost to normal. Most will continue to do well unless they develop toxic reactions to their medications, Eron says.

But Eron knows from experience that these drugs aren’t perfect. “In general, only about half of the patients who start on therapy have the result that we want,” he says. In many others, the HIV develops mutations that make the virus resistant to one or more of the 15 approved anti-HIV drugs. Because there are no proven regimens to fight drug-resistant HIV, doctors find themselves using trial and error. “We’re struggling,” Eron says. “You know that people have virus that’s not fully suppressed, even though in general they feel relatively well. You know that if you don’t do something, their immune system is gradually going to decline. But there’s no real road map.”

Those patients, Eron says, are the reason to look for new classes of drugs that target a completely different part of HIV’s armor. Carolina’s clinical trials unit is one site testing T20 and T1249, drugs developed by Trimeris, a company in Research Triangle Park. These drugs are fusion inhibitors, which means that they block the HIV protein from fusing with the T-cell—the immune-system cell that HIV takes over and destroys. About 100 people nationwide have taken T20, some for as long as six months, and so far it has worked well and seems to be safe. “I think it’s one of the first drugs in a long time, since the protease inhibitors, where we’ve shown that it inhibits the virus at a different target and that it consistently works in humans,” Eron says.

The next step is figuring out what combination of other drugs will enhance T20. “We know from past experience that if we just give one drug, the virus will quickly become resistant to it,” Eron says. Resistance happens because HIV constantly replicates—makes copies of itself—millions of times a day, says Swanstrom, who in addition to his vaccine work also studies the life cycle of the virus. He explains that while HIV is replicating, it’s also randomly creating mutations—a small change in some part of its RNA sequence.

Many of these mutations weaken the virus, Swanstrom says, and they’ll die out unless something makes it easier for them to stay around. “But if a mutation just by chance happens to be near the active site of an enzyme where a drug was binding, you end up with a drug-resistant virus,” Swanstrom says. Sometimes it’ll take only one mutation for a copy of the virus to become resistant to a particular drug; with other drugs it may take several different mutations.

These mutant strains usually can’t take hold if anti-HIV drug levels remain high enough in a patient’s body to stop replication. But if drug levels fall, the resistant strains have a greater chance of surviving. Since small amounts of the drugs are present, the virus mutants that live and prosper are likely to be those that can survive in the presence of those drugs. But meanwhile, the medication is still suppressing the normal strain of the virus, so over time, the drug-resistant strains can become dominant in the person’s body and grow, evolving even higher levels of resistance. When that happens, those particular anti-HIV drugs become useless for treating that patient. And even worse, sometimes a mutant strain will be cross-resistant—its mutations will cause resistance to more than one drug.

Drug levels can fall for several reasons. Two drugs can interact in a way that lowers drug levels. And there is great variability in the way people metabolize drugs. “Different people can have very different drug levels even while taking the same medicines,” Swanstrom says, “and this is largely unaccounted for in our use of anti-HIV drugs.” Another way drug levels can drop is if patients don’t follow dosing requirements.

So when patients first begin anti-HIV therapy, it may be their best chance to stop replication of the virus. If they don’t adhere strictly to their medication regimens, they increase their chances of developing resistant virus. But following the dosing requirements can be daunting. One drug requires six tablets twice a day and must be refrigerated, while another requires an empty stomach and that the patient drink one and a half liters of fluid daily. And most patients take three or more different types of drugs—anywhere from 20 to 50 pills a day. Also, side effects can make tolerating the medication difficult.

Carol Golin, research assistant professor of medicine, and Andrew Kaplan, associate professor of medicine, have been tracking patients’ adherence to these strict regimens. Previous studies have shown that in general, patients tend to overestimate how well they do at taking any type of medicine. To help correct for that, Golin and Kaplan are using a commercially available pill bottle equipped with a computer chip that records the time and date whenever the bottle is opened.

As with other studies, they’ve found that patients’ trust of their doctors is the best predictor of whether they’ll take their medications. Preliminary data also show that if patients increase their adherence by just 10 percent, they’ll get about a fourfold decrease in viral load. With this information, doctors can help patients set goals. And, Golin says, doctors could use the data to help patients recognize patterns—that they miss medication on weekends, for instance, or when they travel.

Ensuring that patients follow drug regimens may also help keep the epidemic from becoming more dangerous. Drug-resistant HIV can be transmitted. A study led by Eron showed that some patients had resistant virus in their semen despite taking anti-HIV drugs. And in a study of North Carolinians with primary infections—those newly infected with the virus—Eron and collaborators at Duke have found two people carrying a resistant strain of HIV. These people had never taken anti-HIV drugs, so the resistant virus must have been transmitted to them by someone else. They were resistant to only one drug, AZT, but researchers elsewhere have found people with primary infections of strains that are resistant to all classes of drugs.

In other efforts to understand resistance, researchers are exploring the possibility that HIV mutates in different ways in different parts of the body. Cohen explains, “It’s not all one petri dish. There’s the brain, the lymph nodes, the genital tract. Different environments, different rates of mutation.” So even though the virus is undetectable in the blood, there may still be infectious virus—even drug-resistant virus—in the genital tract. Cohen, Swanstrom, and Susan Fiscus, associate professor of microbiology, are studying how HIV evolves in the semen of a group of patients. Cohen’s team tracks patients’ health and collects specimens, Fiscus measures their viral load, while Swanstrom tracks the exact changes in the virus’ RNA sequence. Cohen thinks that the genital tract may be the most important compartment to study. “In the end,” he says, “it’s the genital secretions that are going to cause infection in the next person.”

And that next infection is what the people who study and treat HIV would like to prevent. While HIV isn’t the death sentence it once was, it’s not easily controlled. “As I learn more about HIV,” Davis says, “I realize what a horrible virus it is.”

Centers for a Microbial World

Infectious diseases aren’t going to go away. “We live alongside a microbial world,” says Myron Cohen, director of the new Center for Infectious Diseases at Carolina’s School of Medicine. The center, approved last May, organizes and coordinates clinical and research activities in infectious diseases, including HIV. “We hope the center will offer some unique opportunities for investigators from different disciplines to come together,” Cohen says. Cohen is also proud of UNC-CH’s numerous efforts in preventing and treating HIV and other sexually transmitted diseases. They include a National Institutes of Health Fogarty International Center, which trains researchers and clinicians in prevention of HIV and other sexually transmitted diseases, and an HIV Prevention Network site in Malawi, South Africa.

UNC-CH also houses one of 17 Centers for AIDS Research (there is also one at Duke University) funded by the National Institutes of Health. Directed by Ron Swanstrom, Carolina’s center provides HIV researchers with such resources as starter grants, clinical and core lab facilities, and biostatistics tools. Swanstrom says, “We’re trying to offer people a rich palette of tools to do their research.”

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