Uncommon HIV complication may shed light on treatment for incurable lung disorder
One of the difficult complications of HIV infection is the development of pulmonary hypertension, characterized by high blood pressure in the lungs that can lead to remodeling of the heart and shortness of breath. It can eventually kill a person within two years of diagnosis.
"About one percent of people with HIV infection develop pulmonary hypertension," said Lewis Rubin, MD, professor of medicine at the University of California, San Diego. "In some cases the shortness of breath and the diagnosis of pulmonary hypertension is the presenting complication of HIV disease."
Rubin, director of pulmonary and critical care medicine at UCSD, is working on a new drug to combat pulmonary hypertension. Bosentan has shown in clinical trials to increase the ability of patients to exercise, an indication that their lung performance is improving. Bosentan is an endothelin receptor blocker. Endothelin is believed to play a detrimental role in lung function by constricting blood vessel flow to the lungs and by causing the proliferation of cells that clog the blood vessels.
About 100,000 people in North America and Europe suffer from this incurable lung disorder, often caused by secondary diseases such as HIV or scleroderma.
Exactly how pulmonary hypertension develops is unknown, but Rubin said treatment of HIV patients with pulmonary hypertension is giving researchers some clues. "When HIV patients are treated with highly active antiretroviral therapy (HAART)," Rubin said, "We have seen some very dramatic regression of pulmonary hypertension. We are investigating why this happens."
Rubin said there have been suggestions that pulmonary hypertension is activated by a viral infection, so the use of HAART to control HIV might also be controlling the viral cause of the lung disorder.
3-in-1 drug approved
The United States Food and Drug Administration has approved the triple nucleoside analog combination tablet Trizivir from Glaxo Wellcome. Trizivir contains zidovudine, lamivudine and abacavir in one tablet. Trizivir can be taken as one tablet in the morning and one tablet in the evening without regard to food or water intake.
In trials such as the Atlantic Study, the use of the triple-nucleoside analog has been shown to compare well with HAART regimens that contain protease inhibitors and non-nucleoside analogs in reducing circulating HIV to levels below standard quantification limits.
However, abacavir has been associated with a serious adverse event, a hypersensitivity reaction that can be life threatening and has been fatal in some cases. It is characterized by fever, skin rash, fatigue and gastrointestinal symptoms, such as nausea, vomiting, diarrhea or abdominal pain. Respiratory symptoms such as dyspnea, pharyngitis or cough may also occur. In clinical studies, hypersensitivity reaction has been observed in approximately 5 percent of patients.
Researchers note frequently that one of the keys to controlling HIV is to simplify the regimens and reduce the pill burden on patients. Some HIV regimens require as many as 20 tablets daily. Some of these drugs have dietary restrictions as well.
"Trizivir offers some patients the possibility of a regimen as simple as one pill twice a day. For others, it offers them the possibility of simplifying the rest of their existing regimen," said Peter J. Ruane, MD, an HIV researcher at Tower Infectious Diseases Medical Associates Inc., Los Angeles.
More insights into HIV
Proteins that help clean and organize the inside of certain T cells may assist HIV in spreading through the body, scientists from the National Institute of Allergy and Infectious Diseases (NIAID) have discovered.
Reports in the Proceedings of the National Academy of Sciences (Nov. 21, 2000), implicate a collection of housekeeping proteins, collectively called the ubiquitin-proteasome system, in spreading HIV from one cell to another.
"We know more about HIV than about any other virus, and yet it continues to reveal new secrets," states Anthony S. Fauci, MD, director of NIAID. "This discovery provides another example of how HIV manipulates T cells for its own survival and sheds light on a poorly understood type of virus-cell interaction."
The proteasome is the cell's garbage disposal, collecting and destroying old or damaged proteins, or proteins that are no longer needed. Ulrich Schubert, PhD, a visiting scientist in NIAID's Laboratory of Viral Diseases, and colleagues used chemicals to shut down the ubiquitin-proteasome system in HIV-infected CD4-positive T cells is system, and then compared the behavior of HIV in treated and untreated cells.
The results showed significant changes in the ability of the virus to exit CD4-positive T cells and infect neighboring cells. When HIV particles exit the cell in a process called budding, they normally wrap themselves in a piece of the cell's membrane as they leave. The departing viruses therefore have an envelope that can fuse with the membranes of nearby cells, allowing the virus to enter. When chemicals block the proteasome, however, many of the budding virus particles failed to pull their stolen membrane loose as they tried to exit the cell, leaving them trapped on the surface.
"Of the viruses that do manage to escape the surface, many fail to complete the biochemical changes that usually occur after they leave the cell, making them less able to infect new cells," said Schubert, who also maintains a laboratory at Heinrich-Pette Institut in Hamburg, Germany.
Jonathan Yewdell, MD, chief of the laboratory section in which Schubert's research took place, cautions that developing an anti-HIV drug that blocks the proteasome is unlikely. "The proteasome is important for almost all cellular functions, so such drugs would be toxic to the cell." But Yewdell said that thorough understanding of the interactions between HIV proteins and the ubiquitin-proteasome system may in the future reveal new ways to attack the virus.
Microbicide from seaweed
Scientists are currently working on a seaweed gel that will prevent transmission of HIV, during intercourse. The gel would be inserted into a woman's vagina before sex, and thus would have the advantage of giving women control of the product, unlike condoms which require negotiated use.
There is no vaginal microbicide that is effective in preventing transmission of HIV.
The New York-based Population Council has been working for about 10 years on the product, carrageenan, which has the trademark name Carraguard or PC-515. The gel, long used in anti-aging cosmetics and in the food industry, does not kill HIV but prevents the virus entering human cells.
Human trials have now started in Thailand and South Africa to test whether women are comfortable with the product and to check for side-effects. The product is derived from red seaweed found off the coast of Chile. It contains sulphated polysaccharides, known to have antiviral properties.
General HIV/AIDS Websites of interest:
HIV InSite, The University College at San Francisco hivinsite.ucsf.edu/
ÆGiS, online bulletin boardhttp://www.aegis.com/
CDC National Prevention Information Network. A service of the National Center for HIV, STD and TB Preventionhttp://www.cdcnpin.org/
AIDS Infosource, educational resource, NorthStar Medical Centerhttp://www.aidsinfosource.com/
Johns Hopkins Web Servicehttp://www.hopkins-aids.edu/