Tumor
Suppressor Blocks Viral Growth
in Natural HIV Controllers
Elevated
p21 expression blocks key steps in viral life cycle
Elevated
levels of p21, a protein best known as a cancer fighter,
may be involved in the ability of a few individuals to control
HIV infection with their immune system alone. In a paper
in the April edition of the Journal of Clinical Investigation,
researchers from the Massachusetts General Hospital (MGH)
Infectious Disease Division and the Ragon Institute of MGH,
MIT and Harvard report that CD4 T-cells from HIV controllers,
while capable of being infected, can effectively suppress
key aspects of the viral life cycle, an ability that may
be associated with increased expression of the p21 protein.
Preliminary results of this study were presented at the
October 2010 Infectious Diseases Society of America meeting.
"Finding that p21 -- best known for its role as a tumor
suppressor -- is strongly upregulated in CD4 cells from
elite controllers and that experimentally knocking out the
protein substantially increases those cells' susceptibility
to HIV was quite surprising and suggests there may be shared
mechanisms of immune defense against cancer and HIV,"
says Mathias Lichterfeld, MD, of the MGH Infectious Disease
Division, the paper's corresponding author.
About one in 300 individuals infected with HIV are naturally
able to suppress viral replication without antiviral drug
treatment, an ability that keeps viral levels extremely
low and prevents the immune system breakdown that characterizes
AIDS. In those individuals termed elite controllers, viral
levels cannot be detected with standard assays, while in
other viremic controllers, levels remain below 2000 copies/ml.
In 2006 Ragon Institute investigators established the International
HIV Controllers Study (www.hivcontrollers.org)
to investigate immunologic characteristics that may underlie
this rare ability. To date, more than 1,500 controllers
worldwide have been enrolled in the study.
In November 2010, Ragon investigators reported in the journal
Science that mutations in an important immune system
protein explain some but not all of the ability to control
HIV infection. The current study was designed to investigate
additional mechanisms influencing natural HIV control and
focused on factors that interfere with viral growth within
CD4 T-cells, the virus's primary target. The researchers
first confirmed that HIV growth is much less efficient in
cells from elite controllers than in those from individuals
with progressive HIV infection or uninfected blood donors.
CD4 cells from viremic controllers also had reduced viral
replication, although not to the extent seen in elite controllers.
Because previous studies have found that elevated levels
of the tumor suppressor protein p21 -- which blocks a cellular
enzyme required for viral replication -- reduced HIV replication
in other immune cells, the researchers examined the protein's
expression in CD4 T-cells. The experiments revealed that
levels of p21 and its associated mRNA were 10 to 20 times
higher in CD4 cells from HIV controllers. In addition, experimentally
knocking out the protein significantly increased viral replication
in CD4 cells from HIV controllers.
"We found that p21 expression affects at least two
stages in the HIV life cycle inside CD4 T cells. It blocks
reverse transcription -- one of the earliest stages at which
viral RNA is converted into DNA, a necessary step in making
the building blocks for new viruses -- and it inhibits the
production of new viral RNA molecules derived from the viral
DNA integrated into the cells' chromosomes," says Lichterfeld.
"This ability to independently block two different
events seems to enhance p21's effect in limiting the production
of new viruses."
"The challenge now is to understand why p21 is more
strongly expressed in HIV controllers," he continues.
"Once we know that, we may be able to induce increased
p21 expression in a broader patient population, which may
produce greater resistance to HIV. It looks like immune
protection against HIV is mediated by a combination of different
mechanisms, and p21-mediated inhibition of HIV replication
may be an important piece of the puzzle." Lichterfeld
is an instructor in Medicine at Harvard Medical School.
Investigator affiliations:
Ragon Institute of Massachusetts General Hospital, Massachusetts
Institute of Technology and Harvard University, Boston,
MA; Howard Hughes Medical Institute, Chevy Chase, MD; Program
of Biological Sciences in Dental Medicine, Harvard University,
Cambridge, MA; Department of Biochemistry and Molecular
Medicine and Division of Nephrology, Department of Medicine,
University of California at Davis, Davis, CA; Department
of Molecular Oncology, Lee Moffitt Cancer Center, Tampa,
FL; Infectious Disease Division, Massachusetts General Hospital,
Boston, MA.
