Powerful anti-HIV drugs have come tantalizingly close to eradicating the virus from people, driving the blood level of HIV so low that standard tests cannot detect it. But no one has been cured: the virus comes roaring back in everyone who stops taking the drugs. A new study has identified one of HIV's main hideaways, raising intriguing possibilities about how to remove it.
The work addresses a mystery first reported in 2006 by the lab of Robert Siliciano, a virologist at Johns Hopkins University in Baltimore, Maryland, who has developed the most sensitive test to find HIV. Siliciano's group first isolated HIV from treated people who had been "undetectable" for at least 6 months. The team then sequenced the genetic material from these viruses and tracked down the infected cells that produced them. The researchers identified some white blood cells with CD4 receptors-the conductor of the immune system's orchestra and the main target of the virus—that held identical HIV sequences in their chromosomes. But in most people they studied, the virus in the blood did not match the sequence in the CD4 cells, indicating that HIV was hiding elsewhere.
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A team led by virologist Kathleen Collins of the University of Michigan, Ann Arbor, now has evidence that HIV hangs out inside bone marrow. Specifically, they found the virus in hematopoietic progenitor cells (HPCs)—the mother of all immune system cells.
Collins and colleagues first established that HPCs could be infected with HIV. Using HPCs from umbilical cords and commercial labs, the researchers demonstrated in test-tube experiments that the virus not only infected the cells but also could remain latent. This means that the virus does not copy itself, a capability key to forming what's called a reservoir. The virus in latently infected cells, Collins explains, does not trigger an immune response and remains impervious to anti-HIV drugs.
To determine whether HPCs actually harbor the virus in infected people, Collins's team worked with a hematologist who removed HPCs from the bone marrow of 15 HIV-infected volunteers. The researchers report today in Nature Medicine that they found the virus in HPCs from all six people with high levels of HIV in their blood. And of the nine people who had undetectable levels of virus for at least 6 months, four carried HIV-infected HPCs. Collins says she suspects that the other five people also had latently infected HPCs, but the test was not sensitive enough to detect the virus because it infects few cells and they only had small samples from each person.
"Eradication efforts will only be successful if all of the reservoirs for HIV are identified and eliminated," says Siliciano. The new study helps solve the mystery of where HIV hides out, he says, although there may be other undetected reservoirs.
Collins says the hope now is to develop drugs that specifically rattle latent HPCs, forcing them to produce virus, which will lead to their death and, eventually, drain this reservoir. "The challenge is certainly daunting," says Collins. "But what's more likely, a vaccine or eradication? I used to think it was a vaccine. Right now, I'm not so sure."