Drug resistant HIV allows body to continue producing virus-fighting cells, Glastone finds

HIV that has become resistant to powerful drugs called protease inhibitors may
not be a dire sign of decline after all, researchers from the Gladstone
Institute of Virology and Immunology have shown. Published in the June issue of
Nature Medicine, the study shows that drug-resistant HIV is less able to infect
the thymus, the organ that churns out virus-fighting T cells. These patients
can then continue to produce new T cells even in the face of high viral loads.

“It’s potentially good news for patients who are on drugs and tolerating them,”
said lead author Cheryl Stoddart, PhD, staff research scientist at Gladstone.
“Just because they have high viral loads and drug-resistant virus, it doesn’t
necessarily mean that their T-cell counts are going to plummet.”

The presence of drug-resistant virus could just be a sign of the drugs at work,
said senior co-author Joseph M. McCune, MD, PhD, an investigator at Gladstone
and a professor of medicine, microbiology and immunology at the University of
California, San Francisco.

“Though the drugs don’t eradicate the virus, they’re effective in treating the
disease because they produce drug-resistant virus, which appears to be much
less capable of causing damage to the thymus,” McCune said. “The study is
informative in that it gives us a clue as to how patients and virus might be
able to coexist.”

Many AIDS patients take protease inhibitors to stop HIV from growing and
spreading throughout the body. Often, however, the virus mutates and becomes
resistant to the effects of these drugs. Once drug-resistant, HIV can divide
and grow, increasing its numbers in the blood. In the case of virus resistant
to another class of drugs that includes AZT, the viral load normally increases,
leading to a decrease in the number of T cells. The opportunistic infections
characteristic of AIDS, which is caused by HIV, soon follow.

However, in patients with HIV that is resistant to protease inhibitors, earlier
research from co-author on the Gladstone study Steven Deeks, MD, UCSF assistant
professor of medicine at San Francisco General Hospital Medical Center, has
shown that the T-cell counts often remain high. A clue to this phenomenon came
when researchers previously discovered that the drug-resistant viruses don’t
replicate as well in various cells. The new study shows that this impairment is
much greater in the thymus, which remains healthy and can continue to supply
the body with plenty of T cells.

In the study, Stoddart and her research team inoculated both non-resistant
(“wildtype”) virus and drug-resistant virus into human thymus, which was
implanted into mice. Weeks later, the wildtype virus grew substantially and
began depleting the thymus of its cells. Drug-resistant virus, on the other
hand, barely replicated and didn’t tamper with the cells of the thymus.

“The difference in the way the virus grew could not be more extreme,” Stoddart
said.

In another experiment, the researchers added virus to cell cultures derived
from human thymus. They again measured viral replication by detecting p24, an
HIV protein, in the cells. Whereas many cells were infected by the wildtype
virus, far fewer were infected by the drug-resistant virus.

They found the same with virus obtained from actual patients. Wildtype HIV
isolates taken from patients when they were not on protease inhibitors were
readily able to divide in the thymus cells. Drug-resistant virus, taken from
the same patients when they were on protease inhibitors, didn’t grow well at
all. On average, 12 times fewer thymus cells became infected with
drug-resistant virus than were infected with wildtype virus.

The researchers also measured the size of the thymus in 14 patients using a CT
(computed tomography) scan. Many of those who had developed resistance to
protease inhibitors had more abundant thymus tissue than would be expected of
people their age, suggesting that the thymus was indeed spared in these
patients.

Next, the researchers will focus on studying the thymus cells to figure out
exactly why the virus is less able to infect them. 

Co-investigators of the study include Staff Research Scientist Teri J. Liegler,
PhD, Senior Research Associate Valerie D. Linquist-Stepps, Research Associate
Matthew S. Hayden, and Investigator Robert M. Grant, MD, PhD, all of Gladstone.
Research Director Francois Clavel, MD and Research Scientist Fabrizio Mammano,
PhD, both of the Institut National de la Sante et de la Recherche Medicale
(INSERM), Hopital Bichat-Claude Bernard in France, were also involved.

This study was funded by grants from National Institutes of Health and UCSF
Center for AIDS Research.

The Gladstone Institute of Virology and Immunology is one of three research
institutes that comprise The J. David Gladstone Institutes, a private
biomedical research institution affiliated with UCSF. The institution is named
for a prominent real estate developer who died in 1971. His will created a
testamentary trust that reflects his long-standing personal interest in medical
education and research.