Shifty HIV Thwarts
All AIDS Vaccine Attempts

By Lidia Wasowicz
UPI Senior Science Writer

U.S. government researchers said Wednesday they have uncovered an ingenious ploy by the shifty AIDS virus that for two decades has thwarted intense international efforts to develop an effective vaccine against the deadly scourge.
The human immunodeficiency virus, which causes acquired immune deficiency syndrome, apparently changes shape of a critical component of its coating to protect itself against any defenses the body can muster, they found. The swiftly shifting strategy leaves the virus nearly invulnerable to an antibody attack -- be it directed by the infection-intolerant immune system or prodded by a vaccine, the scientists reported.
As primary defenders against disease, antibodies attach themselves to invaders, such as HIV, each protein hooking up with its enemy target. Just as a key fits a specific lock, so antibodies "bind" to matching molecules on the foreign agent's surface, disabling the intruder and sending signals to marshal other immune forces to finish the job.
To evade the antibody faction of the immune army, HIV resorts to what researchers describe as conformational masking. The subterfuge involves altering the shape of a crucial HIV protein, called gp120, throwing up an energy barrier to sidetrack the antibodies sent to destroy it.
The survival tactic comes from HIV's large bag of tricks aimed at confounding the immune system's complex network of cellular sentries, which detect ailment- inflicting agents, and soldiers, which attack and annihilate them, scientists said.
"The virus has mechanisms by which it can change quickly to adapt to whatever immune pressures are placed upon it," lead study author Peter Kwong, a National Institutes of Health vaccine researcher, said in a telephone interview. "It has such a high rate of evolution, it may at this moment be evolving entirely new mechanisms."
Although the findings expose HIV as a formidable opponent, they also suggest it is not an insurmountable one, researchers told United Press International.
"These findings really develop a new concept for immune system evasion by the virus, and researchers now have to develop the right tools to test the concept and evaluate the possibilities for a new vaccine," said Ted Jardetzky, Soretta and Henry Shapiro Research Professor in Molecular Biology at Northwestern University in Evanston, Ill., who analyzed the results.
"This could be a very large step towards a vaccine, but we will only know after the ideas ... are put to the test," he told UPI.
The search for a cure and an effective AIDS vaccine has intensified with the lengthening of the global casualty list. Although new AIDS diagnoses and deaths have plummeted in many developed countries, the epidemic continues to rampage unabated through impoverished areas of the Third World, particularly Sub- Saharan Africa, home to 95 percent of the 40 million humans infected with HIV or living with the full-blown disease.
Last year, officials of the United States Agency for International Development reported 5 million new HIV infections and 3 million AIDS-related deaths worldwide. In 1999, the disease claimed 2.6 million lives, a record at the time.
Since the human disease, and its monkey counterpart, were identified in 1980, an estimated 60 million people have been infected with the AIDS virus, and nearly half of them -- 24.8 million -- have died, according to the U.N. AIDS program.
In the United States, the 20-year AIDS death toll stands at 467,910, including 5,257 children under age 15. An estimated 320,000 Americans are living with the disease and another 500,000 are infected with the virus, said a spokesman for the Centers for Disease Control and Prevention in Atlanta.
Over the years, scientists fighting the war on AIDS have devised an array of drug therapies that, although extending lives, do so at a high cost -- both literally and figuratively. Expensive and causing an array of severe side effects, the treatments exact a price that bespeaks the need for an alternative approach.
Many scientists hold out hope for an AIDS vaccine that would give the immune system a practice run in recognizing and fighting off the hostile microbes so it could ward off the real invasion more readily.
Yet, this promising approach is beset with a plethora of pitfalls.
"Despite two decades of research, HIV has defied immunologists' best efforts to develop a broadly protective vaccine," Jardetzky pointed out.
Researchers using a variety of methods have developed some two dozen experimental anti-HIV vaccines, some of which have gone to clinical trial, but thus far the results have been disappointing.
In general, a vaccine should cause the immune system to produce antibodies and/or special immune system blood cells that can suppress or kill the infectious disease-causing organisms. In a report published in the Dec. 12 issue of the British journal Nature, Kwong and colleagues at the Vaccine Research Center at the National Institute of Allergy and Infectious Diseases in Bethesda, Md., present a new explanation of why that goal has proven elusive in AIDS vaccine research.
Working with human HIV and immune cells, they tracked an unusual mechanism that appears at the root of the extraordinary evasiveness of the resourceful and resilient organism.
"HIV clearly is a very unusual virus," Kwong, chief of structural biology, told UPI. "There are not many persistent viruses that evade the immune system to this degree."
A close-up look at antigenic properties of the HIV protein gp120 provided a clue to the virus's seeming invulnerability. The protein plays a key role in securing HIV's entry into human immune cells targeted by the virus. The ravaging of these key infection fighters leads to a hallmark of AIDS: a hapless defense system unable to ward off often lethal opportunistic infections.
Normally, entry by an intruder triggers the production of antibodies that recognize major features of the attacker and latch on with a deadly grip. The rhinovirus, cause of the common cold, for instance, stands not a prayer of surviving more than a week or two. Why don't antibodies come to the rescue when HIV invades?
When in danger of being recognized by antibodies set on its destruction, the gp120 protein changes contours at the site where they could do the most harm, thereby diffusing the danger, the researchers found.
"It took us over four years to figure this out," Kwong told UPI.
The investigators discovered a strategy that appears to be unique to HIV: the virus erects an "energy barrier" impregnable to the antibody contingent. By altering the shape of the viral envelope, HIV fools the advancing antibodies and foils their attempt to put it out of commission. The structural shift forces the antibodies to expend energy that normally would be reserved for the attach-and-destroy mission into recognizing and readjusting to the changed landscape at the landing site.
"You might compare this to countermeasures that fighter jets use to confuse surface-to-air missile attacks," Jardetzky explained. "If the virus is very sophisticated in its countermeasures, we need to understand those countermeasures in detail to circumvent them and develop new ways to attack the virus."
The finding marks a major advance against HIV, scientists said.
"It is important for scientists, both at the fundamental level of considering how the immune system and the virus work, and for those scientists who are actively trying to develop practical vaccines," Jardetzky said. "The important message is that we are continuing to reveal the mechanisms that make HIV so difficult to control, and this deeper understanding of both the virus and the immune system will be important to defeating this problem."


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