Stem cells: home of HIV?
Posted by Jef Akst [Entry posted at 7th March 2010 06:00 PM GMT]
Human immunodeficiency virus (HIV) can infect bone marrow cells -- including, possibly, hematopoietic stem cells, according to a study published online on (March 7) in Nature Medicine.
The findings suggest the virus can hide in an inactive state for long periods of time, evading treatment, even in individuals without detectable viral loads.
"It's a little bit surprising to see that [HIV infects] progenitor cells, and [possibly] stem cells as well," said virologist Michael Bukrinsky of The George Washington University in Washington, DC, who was not involved in the research. It's a "novel and important" discovery that "will have big implications for pathogenesis of the disease and potential treatment of these patients."
Even patients who respond to highly active antiretroviral therapy (HAART) can harbor undetectably low viral loads, which can be reactivated later in life to cause a resurgence of the disease. Resting T cells can conceal such latent infections, and are the only well established and characterized HIV reservoirs. But a recent study found circulating viral genomes that differ from those found in T cells, suggesting that additional reservoirs may also exist.
When virologist Kathleen Collins of the University of Michigan in Ann Arbor and her colleagues exposed hematopoietic progenitor cells (HPCs) from bone marrow to HIV, some of the cells were quickly infected and killed by the virus. The team then pushed the progenitors to differentiate -- mostly into an antigen-presenting type of white blood cell -- and saw "a dramatic increase in viral gene expression," Collins said. These results suggested that HPCs likely harbored a latent form of the virus that could be activated by cellular differentiation. In short, HPCs represented another HIV reservoir.
"To my knowledge, we are the first to find another real reservoir beyond the resting T cell," Collins said.
"It reveals another obstacle" for viral eradication, said virologist Mario Stevenson of the University of Massachusetts Medical School, who did not participate in the study. "It shows us another area that we have to target in order to achieve a cure."
The researchers further confirmed the ability of HPCs to carry a latent infection by identifying HIV in the bone marrow in about 40 percent of patients who had undetectable viral loads for at least 6 months.
In order for cells to be able to maintain the latent virus for long periods of time, Collins said, they must live long enough to survive years of HAART. The discovery of latent infection in HPCs is "suggestive" that the new reservoir may be hematopoietic stem cells, which "we carry for our entire lives," she said. Furthermore, as stem cells have the capacity to self renew, the virus could spread through cell division, Collins added.
However, because of the type of HIV that persisted in HPCs, "I have my doubts of the functionality of these cells as reservoirs," Bukrinsky said. The HPCs infected by HIV predominately expressed chemokine receptor CXCR4, meaning they could only be infected by viruses that bind specifically to that receptor. These forms of the virus generally appear much later in infection than the major CCR5-binding viruses, which are primarily involved in transmission from one person to another, meaning the HPC reservoirs would not likely contribute to the spread of the virus through the population.
On the other hand, he added, because "CXCR4 viruses are more pathogenic than CCR5 [viruses], and HPCs are rapidly killed by the [activated] virus, patients will have some problems, even on HAART treatment, generating new T cells and macrophages."
"It all depends on the numbers," Bukrinsky said -- specifically, "the real percentage of these cells" that maintain a latent infection. With only nine patients in this study, it is unclear how frequently these cells harbor the infection. "This needs to be expanded to a bigger population to generate information about the importance of these reservoirs."
Furthermore, there may be additional reservoirs not yet identified, Stevenson said. "I think this study is going to generate a lot of interest," he said. "Whether it's the end of the story, I very much doubt it."
Ref:
nature.com |
