T Memory Cells May Be Long-Term Viral Reservoir for HIV
Thanks to antiviral therapy, people with HIV are now living long and relatively healthy lives. But if they stop taking their drugs, the virus can rebound, multiplying from hidden reservoirs in the body. Investigators from the Harvard-affiliated Massachusetts General Hospital and the Ragon Institute of MGH, MIT and Harvard may have located HIV’s hiding place, in a small group of T cells with stem-like properties.
According to a recent article in the Harvard Gazette, these T memory cells could be the HIV reservoir that researchers have long sought.
"Most human cells are short-lived, so it has been unclear how HIV manages to stick around for decades in spite of very effective antiviral treatment," Mathias Lichterfeld told the Harvard Gazette. The assistant professor at Harvard Medical School services in the MGH Infectious Disease Division is a corresponding author of a report on the findings receiving advance online publication in Nature Medicine.
HIV normally attacks T cells in the immune system, which have short lives. But when researchers considered the longevity of the virus, they began wondering if it might also infect long-lasting, regenerative stem cells as well, despite the fact that these organ-specific stem cells are resistant to HIV infection. That’s when they came across the T memory stem cells.
"We have discovered that a new group of T cells, called T memory stem cells, are susceptible to HIV and likely represent the longest-lasting cellular niche for the virus," Lichterfeld said.
The Harvard Gazette reported that HIV’s devastating impact on the human immune system is due to its habit of infecting the CD4-positive T cells that direct and support the infection-fighting activities of other immune cells. Subtypes of CD4 T cells have different functions and all are capable of being infected by HIV.
ART keeps the virus from replicating, because most CD4 T cells are short-lived and die relatively soon. But CD4 T memory stem cells can live for decades, and give rise to several types of T cells. This means HIV-infected T memory stem cells could continuously regenerate new HIV-infected cells.
Researchers discovered that the T memory stem cells express both CD4 and CCR5 -- the receptor proteins HIV uses to enter cells -- suggesting that these long-lived cells could be the much-sought HIV reservoir. They then found that these cells, unlike traditional stem cells, could be readily infected with HIV. Investigators found that levels of HIV DNA in patients receiving long-term antiviral treatment were highest in T memory stem cells.
When they compared blood samples taken from patients soon after initial infection with those taken several years later, they discovered that the viral sequences in T memory stem cells were very similar despite almost a decade of treatment. This indicated that the HIV had remained unchanged in these T memory cells; further results showed that the amount of HIV also remained constant, despite viral drops in other T cell subsets.
"Our findings suggest that novel, specific interventions will have to be designed to target HIV-infected T memory stem cells," Lichterfeld told the Harvard Gazette. "Methods of inhibiting stem cell pathways are being studied to eliminate cancer stem cells -- persistent cells that are responsible for tumor recurrence after conventional treatments kill proliferating tumor cells. We are now investigating whether any of the drugs that target cancer stem cells might be effective against HIV-infected T memory stem cells.
"Identifying the reservoirs for HIV persistence is a critical step toward developing interventions that could induce a long-term remission without the need for antiviral medication, or possibly eliminate the virus entirely," he said. "Although a real cure for HIV has been elusive, it is not impossible."