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.