Results Published in January Issue of Neurology


Unique Mouse Model Allows UNMC Researchers to Determine

Most Effective Drugs in Treating HIV-dementia

Two of five commonly used drugs to fight HIV have been shown by University

of Nebraska Medical Center researchers to be effective against hard-to-treat

HIV virus hiding in the brain.

The effectiveness of drugs in the central nervous system was demonstrated

for the first time in a unique mouse model that was developed at UNMCs

Center for Neurovirology and Neurodegenerative Disorders (CNND).

The severe combined immunodeficiency (SCID) mouse model for HIV-associated

dementia is unique in that it allows researchers to test which drugs are

most effective in crossing the blood-brain barrier, the brains natural

defense mechanism, and destroying hidden reservoirs of HIV.

Two drugs found most effective were abacavir, known as Ziagen, and lamivudine,

also known as Epivir or 3TC. They reduced viral levels in the brain by

80 to 95 percent. Also tested were zidovudine (AZT), didanosine (ddI) and

stavudine (d4T), which also crossed the blood-brain barrier but were not

as effective.

All five drugs tested come from a class of drugs known as nucleoside

reverse transcriptase inhibitors (NRTI), which work by preventing the virus

from reproducing. The drugs are commonly used in different combinations,

or drug cocktails, but UNMCs researchers tested the drugs one at a time.

Drug cocktails frequently contain a protease inhibitor combined with AZT

or d4T and 3TC.

Results of the two-year drug study appear in a lead article in the January

issue of Neurology, a leading journal of clinical research of neurodegenerative

disorders. The article is accompanied by an editorial written by Drs. Justin

McArthur and Karl Kieburtz, senior neurologists at the Johns Hopkins Medical

Center and Strong Memorial Hospital.

The $175,000 study was funded by grants from the National Institutes

of Health and Glaxo Wellcome, Inc., a pharmaceutical company based in Research

Park Triangle, N.C. Results of a study of drug combinations is now being

prepared by UNMC scientists.

Researchers know that HIV penetrates the central nervous system soon

after infection and sets up residency in the microglia, the brains immune

system cells. Often, the virus stays dormant in the brain. However, 20

percent of adults and 50 percent of children with AIDS develop HIV-dementia,

a devastating complication that causes serious mental and motor deficits.

In addition to being difficult to destroy, the HIV virus hides in the

brain ready to re-infect a person with the virus once drug therapy is stopped.

A greater danger is that it may mutate into a strain resistant to available

therapies.

The relationship between the amount of virus in the brain and the onset

of HIV-associated dementia is poorly understood, said Howard Gendelman,

M.D., Purtilo professor of pathology and microbiology at UNMC and director

of the CNND.

As we get further along with new treatments and modalities, we understand

that the virus can never be eradicated unless we target the brain, he

said. For many years, scientists have left it alone. They didnt know

how to attack the virus in the brain. They didnt understand how to deliver

drugs that could get into the brain and how to eradicate the virus that

was protected by a perceived impenetrable barrier. There were no laboratory

or animal models that were available to allow testing, said Dr. Gendelman,

senior investigator for the study.

Principal investigator of the study was Jenae Limoges, M.D., assistant

professor, Department of Internal Medicine-Infectious Diseases. She said

that autopsies of the brain provide the only definitive information about

how the virus affected the brain. The only other animal model that exists

for testing HIV drugs is the monkey, which is cumbersome, expensive and

not always reproducible.

Clinically, we can tell if a patient with dementia is getting better

while being treated with these drugs. We can use that to presume that the

infection in the brain is going down, but we dont know for sure, she

said. The SCID mouse model can quickly and easily show us exactly what

these drugs are doing in the brain tissue, because we can directly measure

the number of infected cells.

For the study, human cells infected with HIV were injected into the

brains of SCID mice. Because the mice have no immune system, the human

cells are not rejected. An NRTI drug was then injected into the mouse body.

After a limited amount of time, the brain tissues were examined for infected

cells.

One of the surprising results of the study was that AZT did not perform

as well as expected. Physicians have noted that patients with HIV-dementia

improved while on drug therapies that include AZT. Dr. Limoges believes

this result may be related to the dosage level or differences in metabolism

of the drug in mice.

Another result was that new knowledge about the development of HIV-dementia

was gained through this study. Mice resemble human disease in pathology,

in mechanisms of brain damage and by limited behavioral testing. This suggests

that the HIV infected human cells are secreting toxins and causing damage

to these mouse cells, Dr. Limoges said.

UNMC is the only public academic health science center in the state.

Through its commitment to research, education, outreach and patient care,

UNMC has established itself as one of the countrys leading centers for

cancer research and treatment, solid organ transplantation and arthritis.

Nearly $32 million in research grants and contracts were awarded to UNMC

scientists during the past fiscal year. In addition, UNMCs educational

programs are responsible for training more health professionals practicing

in Nebraska than any other institution.