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Studies Change Common Theories on AIDS

New Views on Link Between HIV and Immune System May Lead to Cure

By Kris J. Thiessen

Infection by the Human Immunodeficiency Virus (HIV) triggers a nearly constant battle between two giants: the body's immune system and a powerful virus capable of replicating at a tremendous rate, according to two studies published yesterday.

The findings, which overturn previous ideas of how the virus attacks the body, could eventually mean a shift in the way doctors treat HIV and AIDS, which the virus causes.

The study, published yesterday in Nature, a prominent science journal in London, contradicts he long-held belief that HIV only explodes into a full-scale attack on the body after years of latency.

Researchers at both the University of Alabama at Birmingham and New York University found that, in fact, billions of viral and immune particles battle each other from the first day of an HIV infection. The fight progresses gradually to death, with the immune system losing a little ground every day.

Harvard researchers said they consider the work a considerable advance in scientists' understanding of AIDS.

"I consider these to be important papers," said Ronald C. Desrosiers, professor of microbiology and molecular genetics at the Medical School. "This research will help to focus researchers into the central question--how can every arm of immune response be up, yet the virus continues to replicate in the face of the immune response?"

The journal's editors have described the discoveries as some of the most significant findings on HIV and AIDS to have appeared in years.

"[The papers] are important because they illustrate the very dramatic, real nature of HIV-1 infection," Desrosiers said yesterday. "It is not a silent, latent infection."

Scientists now believe that the immune system is capable of controlling HIV well enough to keep infected people from having symptoms until late stages of infection, when the immune system has practically lost the battle.

Some new drugs all but stop the AIDS virus in its tracks, but not for long. According to Desrosiers, "within weeks or days, resistant virus appears."

These drugs were used by the researchers to understand the dynamics of HIV production. The researchers correlated the virus growth to the level of CD4, a type of white blood cell, and used three types of drugs to inhibit infection.

"The major observation in our work is the kinetics of virus turnover," said George M. Shaw, professor of medicine at the University of Alabama at Birmingham and author on one of the studies, "namely that the half life of the virus is about two days."

When the AIDS virus was discovered in 1984, AIDS seemed like a routine type of disease. HIV attacks a group of white blood cells, called CD4 or T4 cells, which are an essential part of the body's immune system. AIDS was thought to be direct result of this infection.

In 1986, researchers discovered that far too few T4 cells seemed to be infected. From that finding, the central mystery of AIDS was redefined--how could so few viruses be killing all of the white blood cells?

A Few years ago, the lymph nodes, where T cells come to maturity, were unveiled as a large reservoir of the virus, answering one of the researchers' questions. But then the question of how these cells fit into the slow and systematic destruction of the immune system was highlighted.

Researchers began to see that as time passed, more virus was present and fewer T cells existed. Common theory dictated that the virus worked slowly to destroy the immune system. No one seemed to think that the trend was the result of an ongoing and raging battle of virus versus immune system.

Drs. Ho and Shaw realized that they had a unique opportunity to use powerful drugs to watch the infection in progress by essentially creating a snapshot.

Each team administered the drugs to HIV patients with low T4 cell counts, causing a significant decrease in virus population. The drugs used by the researchers inhibit reverse transcriptase or protease, two enzymes essential to virus reproduction.

Both teams found that within two weeks, all of the AIDS virus in the body were mutated to resist the drug. From this, the researchers were able to calculate that 100 million to one billion new virus particles are produced every day.

When the investigators stopped giving the drug, the body kept producing T cells at high levels, allowing the researchers to calculate that about one billion new T cells were being generated every day.

New Medical Approach

Researchers have long worked to figure out ways to boost the immune system to fight the virus, but Shaw thinks that their results signal researchers to change that approach and others.

"There should be a greater emphasis on drugs that inhibit viral replication," Shaw said. "We can also design shorter trials to test more therapies."

"There are [currently] more than 10 potentially valid therapeutic agents, but each has to be optimized in dosage, at what stage of infection it is first given, and whether it is effective combined with other drugs," Shaw said. "Right now, it can take years to test just two or three drugs whereas [we believe] one can explore the potential in just one or two months."

Shaw's group actually measured the rate of appearance of mutants for one drug, nevirapine, which inhibits reverse transcriptase.

"The population of virus mutants replaces sensitive virus in as little as 14 to 28 days," Shaw said.

In an accompanying editorial, Simon Wain-Hobson of the Pasteur Institute in Paris compares the battle between virus and immune system to life in the city.

"That billions of virions and infected cells can be destroyed every day vividly illustrates the very hostile environment created by the immune system--the meanest of streets are nothing by comparison," Wain-Hobson wrote.

Wain-Hobson also believes the research dictates that anti-HIV drugs should be given to patients earlier in their infection, continuing throughout the infection.

Shaw sees this work as "the first step in what needs to be a series of studies." He believes that HIV and CD4 need to be correlated at all stages of infection, new drugs must be made to combat existing and new enzyme targets, and combinations of drugs must be tested.

"Combinations may cause enhancement of therapy," Shaw said. "One drug may cause the virus to mutate so that it becomes more susceptible to another drug."

Desrosiers said that it is theoretically possible that one drug can be designed where the virus cannot mutate without becoming inactive, but it is "much more likely that combinations of drugs will be a more effective therapy."

Shaw plans to explore the HIV and CD4 relationship at earlier stages of disease, look at cellular targets that harbor HIV and replicate with varying efficiency, and to evaluate the number of pre-existing mutants of HIV.

None of the researchers are claiming a victory over AIDS yet, but studies like these advance the knowledge of how HIV works. Desrosiers said that researchers must "keep at it."

The Battle HIV vs, Immune System

Scientists have shed more light on the rates of replication and mutation of HIV.

  HIV  infected T CellNumber  100 million to 1 billion viruses produced each day.  Two billion infected cells or T cells, which are 5% of the total T cells in the body.After two days  Half of the viruses die and are replaced by roughly in equal amount of new viruses.  Half of the infected T cells die and are replaced by new T cells.Effect of anti-HIV drugs  Initially, over 99% of the viruses can be killed with drugs like nevirapine.  The healthy T cell count increases.After two weeks  After mutations, almost all of the new viruses are drug resistant or immune.  The healthy T cell count decresses and new T cells are infected with the drug-resistant viruses.Source: Natura Magazine, New York Time

In 1986, researchers discovered that far too few T4 cells seemed to be infected. From that finding, the central mystery of AIDS was redefined--how could so few viruses be killing all of the white blood cells?

A Few years ago, the lymph nodes, where T cells come to maturity, were unveiled as a large reservoir of the virus, answering one of the researchers' questions. But then the question of how these cells fit into the slow and systematic destruction of the immune system was highlighted.

Researchers began to see that as time passed, more virus was present and fewer T cells existed. Common theory dictated that the virus worked slowly to destroy the immune system. No one seemed to think that the trend was the result of an ongoing and raging battle of virus versus immune system.

Drs. Ho and Shaw realized that they had a unique opportunity to use powerful drugs to watch the infection in progress by essentially creating a snapshot.

Each team administered the drugs to HIV patients with low T4 cell counts, causing a significant decrease in virus population. The drugs used by the researchers inhibit reverse transcriptase or protease, two enzymes essential to virus reproduction.

Both teams found that within two weeks, all of the AIDS virus in the body were mutated to resist the drug. From this, the researchers were able to calculate that 100 million to one billion new virus particles are produced every day.

When the investigators stopped giving the drug, the body kept producing T cells at high levels, allowing the researchers to calculate that about one billion new T cells were being generated every day.

New Medical Approach

Researchers have long worked to figure out ways to boost the immune system to fight the virus, but Shaw thinks that their results signal researchers to change that approach and others.

"There should be a greater emphasis on drugs that inhibit viral replication," Shaw said. "We can also design shorter trials to test more therapies."

"There are [currently] more than 10 potentially valid therapeutic agents, but each has to be optimized in dosage, at what stage of infection it is first given, and whether it is effective combined with other drugs," Shaw said. "Right now, it can take years to test just two or three drugs whereas [we believe] one can explore the potential in just one or two months."

Shaw's group actually measured the rate of appearance of mutants for one drug, nevirapine, which inhibits reverse transcriptase.

"The population of virus mutants replaces sensitive virus in as little as 14 to 28 days," Shaw said.

In an accompanying editorial, Simon Wain-Hobson of the Pasteur Institute in Paris compares the battle between virus and immune system to life in the city.

"That billions of virions and infected cells can be destroyed every day vividly illustrates the very hostile environment created by the immune system--the meanest of streets are nothing by comparison," Wain-Hobson wrote.

Wain-Hobson also believes the research dictates that anti-HIV drugs should be given to patients earlier in their infection, continuing throughout the infection.

Shaw sees this work as "the first step in what needs to be a series of studies." He believes that HIV and CD4 need to be correlated at all stages of infection, new drugs must be made to combat existing and new enzyme targets, and combinations of drugs must be tested.

"Combinations may cause enhancement of therapy," Shaw said. "One drug may cause the virus to mutate so that it becomes more susceptible to another drug."

Desrosiers said that it is theoretically possible that one drug can be designed where the virus cannot mutate without becoming inactive, but it is "much more likely that combinations of drugs will be a more effective therapy."

Shaw plans to explore the HIV and CD4 relationship at earlier stages of disease, look at cellular targets that harbor HIV and replicate with varying efficiency, and to evaluate the number of pre-existing mutants of HIV.

None of the researchers are claiming a victory over AIDS yet, but studies like these advance the knowledge of how HIV works. Desrosiers said that researchers must "keep at it."

The Battle HIV vs, Immune System

Scientists have shed more light on the rates of replication and mutation of HIV.

  HIV  infected T CellNumber  100 million to 1 billion viruses produced each day.  Two billion infected cells or T cells, which are 5% of the total T cells in the body.After two days  Half of the viruses die and are replaced by roughly in equal amount of new viruses.  Half of the infected T cells die and are replaced by new T cells.Effect of anti-HIV drugs  Initially, over 99% of the viruses can be killed with drugs like nevirapine.  The healthy T cell count increases.After two weeks  After mutations, almost all of the new viruses are drug resistant or immune.  The healthy T cell count decresses and new T cells are infected with the drug-resistant viruses.Source: Natura Magazine, New York Time

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