Impaired replication of protease inhibitor-resistant HIV-1 in human thymus

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 ZDV, 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 wild type 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.

Source: UCSF News

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