HIV primate progress
Researchers at Rockefeller University have successfully altered one gene in HIV-1 to infect monkeys with a human version of virus.
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NEW YORK CITY—Researchers at Rockefeller University have broken new ground in the global race against the spread of HIV/AIDS by successfully altering one gene in HIV-1 to infect monkeys with a human version of virus. According to the researchers, the experiment on simians could bring science one step closer to developing an HIV vaccine for humans.
The findings, published March 2 in the Proceedings of the National Academy of Sciences (PNAS), show that the engineered virus injected into a pig-tailed macaque initially spreads almost as ferociously as in people, and the virus remains detectable for at least six months. Although it does not make the monkeys sick, it does behave similarly to a group of HIV-positive humans (long-term nonprogressors) whose exceptional immune systems are generally able to keep the virus in check.
This study was a close collaboration between lead researchers Theodora Hatziioannou, assistant professor of the Aaron Diamond AIDS Research Center (ADARC), and Paul Bieniasz, head of the Laboratory of Retrovirology at Rockefeller and associate professor at ADARC, along with Vineet KewalRamani and Jeff Lifson, both at the National Cancer Institute of Maryland.
The primary cause of AIDS, human immunodeficiency virus (HIV-1), is a pathogen that is highly specific for humans and generally does not infect or cause disease in other species. This property complicates the generation of animal models that are urgently needed to test new antiretroviral therapies and vaccines.
Generating HIV-1-based viruses capable of replicating and causing disease in macaques would obviously overcome these limitations, but the generation of such viruses has not been straightforward.
The team demonstrated the use of the model by showing that a commonly used antiretroviral drug combination taken briefly before and after an injection of two million infectious units of simian-tropic HIV-1 (stHIV-1), effectively protected the monkeys from the virus.
This important advance formed the basis of the researchers' current research that aims to test the utility of stHIV as an HIV-1 infection model in monkeys and to generate improved derivatives of stHIV by probing further the activity of restriction factors in macaque cells, Rockefeller University researchers say.
"What makes this study revolutionary in the field of HIV research, is it is the first time in HIV-1 research that we have developed a strain called simian-tropic HIV-1 (stHIV-1) which shares 96 percent of its genome with the human version," Hatziioannou says. "The new virus, stHIV-1, spreads almost as quickly after injection as HIV-1 initially does in humans, and persists for several months before it is controlled, in part thanks to a specific class of immune system T cells that if blocked, allow a resurgence of the virus."
If successful, these studies have the potential to generate improved animal models for HIV-1 infection and should revolutionize the development and testing of drug and vaccine interventions, the researchers say. But for stHIV-1 to be useful for testing vaccines, scientists must modify the protein envelope surrounding the virus so it targets the same set of immune cells in monkey as in humans, Hatziioannou points out.
"The virus did not give the monkeys AIDS," Hatziioannou says. "To have a really authentic model, we need to make it pathogenic, make it hotter."
Although the research "provided a better way of testing antiretroviral drug treatments prior to clinical trials in humans, it is not possible to evaluate, at present, the direct impact on HIV/AIDS patients," she says. The next step is to "generate improved versions of our virus that will be able to cause AIDS in animals."
Researcher Bieniasz says, "We're not saying we can save the world with antiretroviral pills, but this model will allow us to start studying the best way to administer prophylaxis and do other experiments on preventing HIV-1 infection that could not be easily done on humans."
The findings, published March 2 in the Proceedings of the National Academy of Sciences (PNAS), show that the engineered virus injected into a pig-tailed macaque initially spreads almost as ferociously as in people, and the virus remains detectable for at least six months. Although it does not make the monkeys sick, it does behave similarly to a group of HIV-positive humans (long-term nonprogressors) whose exceptional immune systems are generally able to keep the virus in check.
This study was a close collaboration between lead researchers Theodora Hatziioannou, assistant professor of the Aaron Diamond AIDS Research Center (ADARC), and Paul Bieniasz, head of the Laboratory of Retrovirology at Rockefeller and associate professor at ADARC, along with Vineet KewalRamani and Jeff Lifson, both at the National Cancer Institute of Maryland.
The primary cause of AIDS, human immunodeficiency virus (HIV-1), is a pathogen that is highly specific for humans and generally does not infect or cause disease in other species. This property complicates the generation of animal models that are urgently needed to test new antiretroviral therapies and vaccines.
Generating HIV-1-based viruses capable of replicating and causing disease in macaques would obviously overcome these limitations, but the generation of such viruses has not been straightforward.
The team demonstrated the use of the model by showing that a commonly used antiretroviral drug combination taken briefly before and after an injection of two million infectious units of simian-tropic HIV-1 (stHIV-1), effectively protected the monkeys from the virus.
This important advance formed the basis of the researchers' current research that aims to test the utility of stHIV as an HIV-1 infection model in monkeys and to generate improved derivatives of stHIV by probing further the activity of restriction factors in macaque cells, Rockefeller University researchers say.
"What makes this study revolutionary in the field of HIV research, is it is the first time in HIV-1 research that we have developed a strain called simian-tropic HIV-1 (stHIV-1) which shares 96 percent of its genome with the human version," Hatziioannou says. "The new virus, stHIV-1, spreads almost as quickly after injection as HIV-1 initially does in humans, and persists for several months before it is controlled, in part thanks to a specific class of immune system T cells that if blocked, allow a resurgence of the virus."
If successful, these studies have the potential to generate improved animal models for HIV-1 infection and should revolutionize the development and testing of drug and vaccine interventions, the researchers say. But for stHIV-1 to be useful for testing vaccines, scientists must modify the protein envelope surrounding the virus so it targets the same set of immune cells in monkey as in humans, Hatziioannou points out.
"The virus did not give the monkeys AIDS," Hatziioannou says. "To have a really authentic model, we need to make it pathogenic, make it hotter."
Although the research "provided a better way of testing antiretroviral drug treatments prior to clinical trials in humans, it is not possible to evaluate, at present, the direct impact on HIV/AIDS patients," she says. The next step is to "generate improved versions of our virus that will be able to cause AIDS in animals."
Researcher Bieniasz says, "We're not saying we can save the world with antiretroviral pills, but this model will allow us to start studying the best way to administer prophylaxis and do other experiments on preventing HIV-1 infection that could not be easily done on humans."
