Study identifies population of stem-like cells where HIV persists in spite of treatment
Recently discovered T memory stem cells may be long-term viral reservoir, potential targets for future treatment
12-Jan-2014 - Although antiviral therapy against HIV suppresses viral replication and allows infected individuals to live
relatively healthy lives for many years, the virus persists in the body, and replication resumes if treatment is interrupted. Now
investigators from Massachusetts General Hospital (MGH) and the Ragon Institute of MGH, MIT and Harvard may have found where
the virus hides - in a small group of recently identified T cells with stem-cell-like properties.
"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," says Mathias Lichterfeld, MD, of the MGH Infectious Disease Division, corresponding author of the report receiving advance
online publication in Nature Medicine . "This question led to the hypothesis that HIV might infect stem cells - the most long-lasting
cells in the body - but traditional organ-specific stem cells, even those that give rise to all immune and blood cells, are
resistant to HIV infection. 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."
HIV has such a devastating impact on the human immune system because it infects the CD4-positive T cells that normally direct and support
the infection-fighting activities of other immune cells. Several subtypes of CD4 T cells have different functions; and all are capable of
being infected by HIV, although antiviral treatment keeps the virus in those cells from replicating. Most of these CD4 T cells are
short-lived and die relatively soon. What is distinct about CD4 T memory stem cells is their ability to live for decades, while
giving rise to several subgroups of T cells. Therefore, HIV-infected T memory stem cells could continuously regenerate new
HIV-infected cells, fueling the fire of HIV persistence in the human body.
The MGH/Ragon team found that T memory stem cells express both CD4 and CCR5 - the receptor proteins used by HIV to enter cells - suggesting
that these long-lived cells could be the long-sought HIV reservoir. They then found that these cells can be readily infected with HIV,
which was unexpected since traditional stem cells resist HIV infection. Importantly, the investigators found that levels of HIV DNA
in patients receiving long-term antiviral treatment were highest in T memory stem cells.
Testing blood samples that had been taken from patients soon after initial infection and several years later revealed that the viral
sequences found in T memory stem cells after 6 to 10 years of treatment were similar to those found in circulating T cells soon after
infection, indicating that HIV had persisted relatively unchanged in T memory stem cells. In addition, the amount of HIV DNA in
these cells remained relatively stable over time, even after long-term treatment caused viral levels to drop 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," says
Lichterfeld, an assistant professor of Medicine at Harvard Medical School. "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," Lichterfeld adds. "Although a real cure for HIV has
been elusive, it is not impossible."
Maria Buzon, PhD, of MGH Infectious Diseases and the Ragon Institute is lead author of the Nature Medicine paper. Additional co-authors
are Hong Sun, MD, Chun Li, PhD, Amy Shaw, Katherine Seiss, Zhengyu Ouyang, PhD, Enrique Martin-Gayo, PhD, Jin Leng, PhD, Florencia
Pereyra, MD, Xu Yu, MD, and Bruce Walker, MD, Ragon Institute; Eric Rosenberg, MD, MGH Infectious Disease Division; Timothy
Henrich, MD, and Jonathan Li, MD, Brigham and Women's Hospital; and Ryan Zurakowski, PhD, University of Delaware. Walker,
the director of the Ragon Institute, is also a Howard Hughes Medical Institute investigator. Support for the study
includes American Foundation for AIDS Research grants 108302-51-RGRL and National Institutes of Health grants
AI098487, AI106468, AI089339, AI098480, AI100699.
The Ragon Institute of MGH, MIT and Harvard was established in 2009 with a gift from
the Philip T. and Susan M. Ragon Foundation, creating a collaborative scientific mission among these institutions to harness the
immune system to combat and cure human diseases. The primary initial focus of the institute is to contribute to the development
of an effective AIDS vaccine. The Ragon Institute draws scientists and engineers from diverse backgrounds and areas of
expertise across the Harvard and MIT communities and throughout the world, in order to apply the full arsenal of
scientific knowledge to understanding mechanisms of immune control and immune failure and to apply these
advances to directly benefit patients.
Contact: Sarah Dionne Sullivan
Massachusetts General Hospital
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