(PHILADELPHIA) – Researchers at the University
of Pennsylvania School of Medicine are the first to
show that a mouse protein, whose human equivalent is related to
defense against HIV-1,
inhibits the infection and spread of a mouse tumor
The study, which appeared online January 28 in advance of its print
publication in Nature,
provides a new model for the discovery and evaluation of anti-HIV
drugs. HIV-1, like the mouse tumor virus, is a retrovirus
which infects immune
system cells. However, unlike HIV-1, the mouse virus causes
“Our study is the first to show that the mouse equivalent
to the human protein, called APOBEC3, actually inhibits a retrovirus
in a live animal,” says lead author Susan
R. Ross, PhD, Professor of Microbiology.
The study is based on a mouse strain that does not have the gene
for mouse APOBEC3, developed by co-author Boris
Matija Peterlin, PhD, University
of California at San Francisco.
In this study, normal mice and mutant mice were injected with
tumor virus (MMTV). Using a sensitive test for virus infection,
the researchers found that lymph
nodes from mutant mice were more infected than normal mice.
At six days after injection, the lymph nodes near the injection
site in mutant mice had four times more of the breast cancer-causing
virus. By 18 days after infection, the virus had spread to other
sites in the mice, and spleen
cells from the mutant mice were seven-fold more infected by MMTV
than spleen cells from normal mice. The research team is currently
waiting to see if mutant mice develop breast cancer at a greater
rate than normal mice.
“Although this study was performed with mice and used a
mouse tumor virus for which there is no human counterpart, the mouse
model of infection we have developed may be useful as a test system
for evaluating drugs that augment the role of human APOBEC3 in defending
against HIV,” says Ross. Since its discovery in 2002, the
human equivalent to mouse APOBEC3 has been shown to defend some
cell types against HIV-1 infection.
Some unanswered questions remain about APOBEC3 and how it can prevent
virus replication and spread. Some cells cannot be infected with
a retrovirus unless the virus has viral
infectivity factor (Vif). Vif is a protein made by viruses like
HIV that binds to APOBEC3 and marks it for destruction.
On the other hand, if APOBEC3 is not degraded
by binding with Vif, it gets packaged into new virus particles.
When these virus particles infect new cells, APOBEC3 causes mutations
in virus RNA
by a process called deamination.
The mutations are so extensive that the new viruses cannot infect
more cells, thus stopping the spread of the virus.
However, in the Nature study, no mutated MMTV virus was
detected in the normal mice. “Thus, APOBEC3 must not use the
deamination activity to mutate and limit the spread of MMTV,”
says Ross. “We plan to study the mechanism of the antiviral
activity in our model system.”
This study was funded by the National
Cancer Institute and the Slovenian
Co-authors in addition to Ross and Peterlin are Chioma
M. Okeoma, from Penn, and Nika
of Ljubljana (Slovenia).
PENN Medicine is a $2.9 billion enterprise
dedicated to the related missions of medical education, biomedical
research, and high-quality patient care. PENN Medicine consists
of the University of Pennsylvania School of Medicine (founded in
1765 as the nation's first medical school) and the University of
Pennsylvania Health System.
Penn's School of Medicine is ranked #2 in the nation for receipt
of NIH research funds; and ranked #3 in the nation in U.S. News
& World Report's most recent ranking of top research-oriented
medical schools. Supporting 1,400 fulltime faculty and 700 students,
the School of Medicine is recognized worldwide for its superior
education and training of the next generation of physician-scientists
and leaders of academic medicine.
The University of Pennsylvania Health System includes three hospitals,
all of which have received numerous national patient-care honors [Hospital
of the University of Pennsylvania; Pennsylvania Hospital, the nation's
first hospital; and Penn Presbyterian Medical Center]; a faculty practice
plan; a primary-care provider network; two multispecialty satellite
facilities; and home care and hospice.