Doctors have long been mystified as to why HIV-1
rapidly sickens some individuals, while in others the
virus has difficulties gaining a foothold. Now, a
study of genetic variation in HIV-1 and in the cells
it infects reported by University of Minnesota
researchers in this week’s issue of PLOS Genetics
has uncovered a chink in HIV-1’s armor that may,
at least in part, explain the puzzling difference –
and potentially open the door to new treatments.
HIV-1 harms people by invading immune system
cells known as T lymphocytes, hijacking their
molecular machinery to make more of themselves,
then destroying the host cells — leaving the infected
person more susceptible to other deadly diseases.
T lymphocytes are not complete sitting ducks,
however. Among their anti-virus defense
mechanisms is a class of proteins known as
APOBEC3s that have the ability to block the HIV-1’s
ability to replicate. Not surprisingly, however, HIV-1
has a counter-defense mechanism – a protein
called Vif that cons the T lymphocytes into
destroying their own APOBEC3.
Suspecting differential susceptibility to HIV-1 might
be related to genetic variations in this system, a
research team led by doctoral student Eric Refsland
and Reuben Harris of the University’s College of
Biological Sciences and Medical School took a
closer look. First, the researchers found that HIV-1
infection boosts the production of one kind of
APOBEC3, APOBEC3H – suggesting it’s a key
player in fighting back. Then, using an experimental
technique known as separation of function
mutagenesis, they discovered that different people
have different strengths/potencies of APOBEC3H,
with some proteins expressed stably and others
inherently unstable. The stable variations, the
researchers found, were able to successfully limit
HIV-1’s ability to replicate if the infecting virus had
a weak version of Vif – but not for HIV-1 viruses
that had strong Vif.
“This work shows that the competition between the
virus and the host is still ongoing,” Refsland says.
“The virus hasn’t completely perfected its ability to
replicate in humans.”
Armed with this clearer picture of the multifaceted
interactions between Vif and APOBEC3, Harris says,
the next step is to figure out how to stop Vif from
disabling the APOBEC3 enzymes. “One could
imagine drugs that stop Vif from binding with
APOBEC,” he said. “This is a bonafide HIV killing
pathway, and we just have to devise clever ways to
activate it in infected persons. Such an approach
could indefinitely suppress virus replication, and
even result in curing it.”
Source: sciencedaily.com