UF Research Yields New Understanding of Drug-Resistant HIV Strains

August 6, 1996

GAINESVILLE—Physicians who treat HIV-positive patients face a daily dilemma: how best to quash a disease caused by a virus that rapidly mutates within the body and quickly resists the drugs used to fight it.

Now, studies by University of Florida AIDS researchers have yielded insight into why the virus is so difficult to treat.

In the June issue of the international journal Virology, UF scientists make the case that drug-resistant strains of HIV likely evolve within an infected individual because of the virus’ predetermined genetic instructions. The virus’ ability to vary itself provides a way for it to escape from surveillance by the immune system — and from attack by the anti-viral drugs used to quell infection.

In the past, physicians have speculated that the hardiest viruses fail to respond to drugs because of some inherent reaction to the medication itself.

Dr. John Sleasman, a pediatric immunologist at UF’s College of Medicine, compares the proliferation of HIV strains to the weeds you might find in your backyard. Say you decide to apply weedkiller in the hope of eradicating them.

The new weeds that emerge afterward could be one of two types: those that actually mutated on their own, a rare occurrence in nature, and those that are naturally resistant to the weedkiller — the ones that spread and take over your yard.

“We’re finding that, like these naturally resistant variants of weeds, HIV features pre-existing variants that can be found within patients even before they receive drugs like protease inhibitors,” Sleasman said. “The implication, then, is that one of the reasons we see development of drug resistance so quickly is due to this “pre-existing condition.”

To best treat the infection, then, researchers must find a combination of drugs that attacks the virus at several places simultaneously, he said.

The recent advent of drugs known as protease inhibitors show tremendous potential for treating of HIV infection and AIDS, Sleasman said.

HIV is the virus that causes AIDS. A person can test HIV-positive but not yet have full-blown AIDS.

“What’s novel about our study is that we show there is natural variation in the HIV genetic structure even before patients are put on drugs, so it’s highly likely that the forms of the virus that emerge after exposure to medications are naturally occurring resistant strains,” Sleasman said.

The UF team includes principal investigator Maureen Goodenow, associate professor of pathology, and Dr. Ben Dunn, professor of biochemistry and molecular biology.

Protease inhibitors work on a completely different part of the viral life cycle than traditional medications like AZT, ddI and ddC. They interfere with an enzyme called protease, which the AIDS virus needs to multiply in the body.

Protease inhibitors appear to reduce the amount of HIV in the blood by 90 percent or more, especially in combination with traditional drugs. They also boost the number of disease-fighting cells produced by the body’s immune system.

Both types of drugs interfere with the virus’ ability to multiply inside the cells of the immune system, but they attack at different stages of the viral life cycle.

Sleasman also recommended that these drugs not be used in patients until absolutely necessary.

“If you don’t have many weeds in your yard, you’re probably better off not using weedkillers, because if you do, the only ones that grow are going to be the resistant ones and they’ll take over your yard,” he said. “As long as the immune system is doing an OK job of keeping the virus in check, it’s probably not a good idea to use heavy-dose antiviral agents, just as it’s not a good idea to take antibiotics unless you really need to because the bacteria that grow are more likely to be resistant.”

UF and the National Cancer Institute are the only two sites in the nation testing protease inhibitors in HIV-positive children. The study is funded by the National Institutes of Health, the American Foundation for AIDS Research and the Pediatric AIDS Foundation.

“As these children are put on these new medications, we will be able to test our hypothesis that the resistant strains of the virus are actually the genetic mutants we predicted from this initial study,” he said.