The long life of a newly discovered stem cell in the blood may be responsible for HIV’s persistence, says new research. For it appears that HIV hides, not just in memory T cells as thought—but in far longer-lived memory T stem cells.
This discovery could result in new anti-HIV therapies more swiftly than usual. For cancer, as well, is thought by many to be most persistent in stem-cell form. And oncologists have been devising therapies against cancer stem cells for years. Those same therapies may work on stem cells harboring HIV.
“Cancer stem cells seem to play a similar role in maintaining [cancers] as T memory stem cells do for maintaining HIV,” Harvard University Medical School Assistant Professor Mathias Lichterfeld told Drug Discovery & Development. Lichterfeld was senior author on the above paper, which was published this winter in Nature Medicine and reported that CD4 T memory stem cells (CD4+TSCM cells) can serve as long-lasting HIV reservoirs. “As such, many of the drugs that are being evaluated for targeting cancer stem cells are now being investigated for their activity against HIV-1 infected T memory stem cells.”
NIH cancer immunologist Nicolas Restifo isolated the memory T cell stem cells in which Lichterfeld’s team found the HIV virus. “It is fascinating and at the same time sort of horrifying to read in the [Lichterfeld] paper that the HIV virus takes advantage of this stem cell-like activity to survive and propagate for long periods of time,” he told Drug Discovery & Development in an email. Still, he added, it is all “reminiscent of the concept that cancer, too, can take on stem cell-like properties to propagate itself forever.” This, therefore, opens the door to shared cancer/HIV therapies.
The anti-retrovirals most HIV patients take today to control HIV don’t cure it. It is well-known HIV infects primarily CD4+ helper T cells, entering primarily via two receptors: CCR5 and CD4. Anti-retrovirals act by halting replication of HIV at various junctures before and after encountering those receptors. But when patients go off anti-retrovirals, HIV roars back, having hidden in latent form in the body.
Until recently, no one has known what cells harbor latent HIV. But Restifo’s discovery in 2011 of a stem-cell subset of CD4+ T cells led the team of Lichterfeld — which also works at Massachusetts General Hospital’s Division of Infectious Diseases — to look for latent HIV reservoirs in that subset. The CD4+ T stem cell (again: CD4+TSCM cell) is a daughter cell of the more common and more multi-potent hematopoietic stem cell (HSC). The HSC can form all the cells of the blood system, whereas the CD4+TSCM only forms CD4+ T cells.
The reason HIV can hide in CD4+TSCM cells may be simple. Stem cells generally are quiescent cells that only begin expanding and differentiating in response to in vivo calls for healing and regeneration. Once done, the cells settle into quiescence again. They are the longest-lived cells in their organs, unlike the vast majority of cells in the body, which are mature differentiated cells with shorter half-lives.
HIV may be able to hide in CD4+TSCM cells for years because anti-retrovirals impair viral replication. If the cells harboring the virus aren’t replicating, the virus apparently can’t, either. Regardless, the recent paper establishes that HIV can infect CD4+TSCM cells.
“This study indicates that CD4+TSCM cells, despite their low frequencies, stand out among other memory CD4+ T cell subsets as the cell population in which long-term HIV-1 persistence is particularly evident,” said Lichterfeld’s report. This is “probably owing to intrinsic cellular programs of these cells that give them superior abilities to self-renew, resist apoptosis, and survive for extremely long periods of time.” Just how long these stem cells last “has not been determined,” Lichterfeld said via email. “That would be technically very difficult. However, there is a consensus that the T memory stem cells are the longest lasting memory T cells.”
Even more undifferentiated, and more multi-potent, organ stem cells appear to actually be resistant to HIV infection, according to many studies. But these CD4+TSCM cells are more differentiated and express the same receptors through which HIV enters CD4 T cells: CCR5 and CD4. This leaves the cells vulnerable to infection, yet invulnerable to cell death by anti-retrovirals.
The Harvard/MGH team first established that CD4+TSCM cells express both CD4+ and CCR5. Then they established the cells are easily infected by HIV, a key discovery given (as noted above) that more undifferentiated stem cells may be resistant to HIV. Indeed, the team discovered that levels of HIV DNA in patients receiving long-term anti-retrovirals were highest in CD4+TSCM cells. In particular, they found that viral sequences in CD4+TSCM cells taken from patients after six to 10 years of treatment were similar to levels in circulating T cells right after infection. Furthermore, the team found the amount of HIV DNA in these cells remained stable, even after long-term treatment forced viral levels down in other T cells. The virus persisted in these cells even after they replicated, or differentiated, which was “an important point of the story,” said Lichterfeld.
The Harvard/MGH group is now trying anti-cancer stem cell drugs on that HIV stem cell subset. “One anti-cancer approach is targeting the wnt pathway,” Lichterfeld said. “Wnt is a molecule that maintains stem cell-like properties of stem cells, including cancer stem cells. A number of clinical studies are now going on in cancer patients with wnt inhibitors. We are testing if these reagents are also effective against HIV-1 infected T memory stem cells.”