Immune response boosted by prior interruptions in therapy
An unusual group of HIV-infected patients who stopped taking antiviral drugs yet continued to suppress HIV replication may have somehow boosted their immune response against the virus by temporary therapy interruptions, researchers from the Aaron Diamond AIDS Research Center at Rockefeller University report. Although scientists strongly advise against halting drug therapy -- because the virus usually comes surging back -- this observation suggests that some HIV-infected people can suppress the virus without drugs if they have strong immune responses.
The study focuses on only six subjects, so its widespread implications for treating the general population of HIV-infected people are unclear. But if researchers can identify the mechanism by which the immune response is strengthened in patients who interrupted treatment, they might be able to design vaccines that infected patients could take to keep the virus at low levels even when medication is halted.
"We don't want people to stop taking anti-HIV drugs," says Gabriel Ortiz, an M.D., Ph.D. biomedical fellow and first author of the paper. "But the observation that has been made is pretty striking, because it does suggest that artificially vaccinating infected patients who are taking drugs may help maintain virus at a low level if they stop taking drugs for whatever reason."
Suppressing HIV at the lowest possible level is important because the amount of virus in an infected person is the most important factor determining how soon he or she develops full-blown AIDS. Anti-HIV drugs have proven to be effective in keeping the virus at undetectable levels, but they must be taken every day for an indefinite period. Many patients have trouble sticking to the regimen because the drugs can have toxic effects and can cause adverse events in the body. In addition, this highly active antiretroviral therapy (HAART) is unaffordable for most HIV-infected people in developing countries.
If scientists could intervene to boost the immune response, more HIV-positive patients could presumably postpone the development of full-blown AIDS. A vaccine having this effect could possibly be administered to infected populations in the third world who do not have access to antiretroviral pills. "Our study suggests that such a vaccine will have to stimulate cell-mediated immune responses against HIV," says Douglas Nixon, M.D., Ph.D., senior author on the paper.
In the study, the researchers identified six patients who, for various reasons, were unable to keep taking pills for HIV; some had stopped and started again, while others had stopped the therapy altogether. All but one of the subjects had begun therapy within four months of infection with HIV, so the virus was suppressed relatively early. The researchers measured in these patients both the level of virus and the level of immune response.
In three of the six patients, the virus remained low for between four and 24 months after stopping drug therapy. The other three subjects had the virus rebound significantly. The researchers noticed that in those patients where the virus was suppressed, there was "a broad and strong" HIV-specific immune response. It appears that temporarily discontinuing drugs allowed the virus to make its presence known just enough to trigger the immune responses.
The study is reported in the Sept. 15th issue of the Journal of Clinical Investigation by Ortiz, Nixon and 17 colleagues at the Aaron Diamond AIDS Research Center. The researchers say follow-up studies are in progress to build on the intriguing results of this study. New trials getting under way in controlled clinical settings will explore the effects of stopping and starting drug therapies for variable periods.
"Right now, we just have an association," Ortiz says. "The exact mechanism as to how these immune responses interplay with the virus is not completely understood, which is why we can't advocate that patients discontinue drug therapy."
The idea of using "pulsed" treatments is not completely new to medicine, having been part of chemotherapy treatments for cancer for quite some time. But this study represents the first sign that intermittent drug treatment for HIV might rally the immune system.
"Gabriel's study, I think, has advanced the field substantially, because we now believe that immunological mechanisms are critical in keeping the virus low after a drug is discontinued," Nixon says. "In a real-world situation where adherence to anti-HIV drugs is difficult and often impossible, it is essential to know what recourse we have to keep the virus at the lowest levels possible." The other co-authors of the paper are Alexandra Trkola, Ph.D., James Binley, Ph.D., Xia Jin, Ph.D., Sebastian Bonhoeffer, Ph.D., Peter J. Kuebler, B.S., Sean M. Donahoe, B.S., Marie-Ainge Demoitie, B.S., William M. Kakimoto, B.S., Tom Ketas, B.S., Brian Clas, B.S., Jonas J. Heyman, Linqui Zhang, Ph.D., Yunzhen Cao, M.D., Arlene Hurley, R.N., John P. Moore, Ph.D., David D. Ho, M.D., and Martin Markowitz, M.D.
This work was supported in part by grants from the National Institute of Allergy and Infectious Diseases, part of the federal government's National Institutes of Health (NIH), and the General Clinical Research Center grant (M01-RR00102) from the National Center for Research Resources at NIH. Ortiz is an M.D.-Ph.D. student and is supported by an NIH Medical Scientists Training and Minority Pre-doctoral Fellowship.
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