HIV CURE

Innovation
HIV Immunity: Genetic Variation And Antiviral Enzymes
Explain Why Some People Are Naturally Immune To HIV
Nov 20, 2014 05:21 PM
By
Susan Scutti
Some people have a particular variation of APOBEC3H, a
gene which produces an antiretroviral protein that protects
cells by inhibiting the replication of HIV. Photo courtesy of
Shutterstock.
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With any virus, even devastating ones like Ebola and HIV,
there are people who are exposed, often repeatedly, but
somehow they never become infected or develop
symptoms of disease. Though doctors have long wondered
why, especially in the case of HIV, only today has a team
of researchers found an explanation . Scientists at the
University of Minnesota studying HIV-1 discovered some
people have a specific variation of a gene, APOBEC3H,
which produces an antiretroviral protein that inhibits the
replication of HIV.
“We have seven APOBEC3 genes within the variants of
human population,” Dr. Reuben S. Harris, a professor in the
department of Biochemistry, Molecular Biology and
Biophysics, explained to Medical Daily. Of these seven
genes, “only APOBEC3H varies within the human
population,” Harris added. APOBEC3H itself has seven
variations, and if you broadly group these into those that
make stable and those that make unstable proteins, Harris
told Medical Daily , “What we found is those that are stable
confer resistance to some forms of HIV.”
This important finding may pave the way to new
treatments and drugs.
Viral Infectivity Factor
Viruses are often described as the ultimate parasite. They
cannot reproduce or sustain themselves on their own, so
they require a host. In the case of the human
immunodeficiency virus, their host-of-choice is T
lymphocyte cells found in the immune system. After
gaining control of the molecular machinery of T-cells, the
virus duplicates itself and then destroys its host. Naturally,
this damages the immune system and so people infected
with HIV become increasingly susceptible to any pathogen
deciding to invade their bodies, including diseases like
cancer.
However, this picture is somewhat simplistic. T
lymphocytes possess their own defense mechanism in the
form of antiretroviral proteins produced by the APOBEC3
genes. In turn, HIV has its own counter-defense — a
protein referred to as viral infectivity factor (Vif), which
tricks T lymphocytes into destroying APOBEC3 enzymes.
For the current study, then, a group of researchers led by
Harris and doctoral student Eric Refsland decided to
examine this interaction closely. They hypothesized that
different levels of susceptibility to HIV-1 might be related
to variations in the gene producing this antiretroviral
protein.
Testing their theory, Harris and his colleagues first
discovered that an HIV-1 infection increased APOBEC3H
proteins. This, then, had to be an important part of the HIV
susceptibility equation. Next, they “essentially took HIV
strains,” Harris told Medical Daily, “And we figured out what
amino acids are required to counteract APOBEC3H.” This
was done by creating mutant probes to test how important
a stable protein compared to an unstable protein might be
when fighting off an HIV infection. “This is key,” Harris told
Medical Daily . “If you can’t generate these mutants, it’s
difficult to interpret the cell data.”
After creating the necessary probes, then, the research
team used cells from donors and found different people
with different genetic variations of APOBEC3H produced
stronger and more stable antiretroviral proteins. The stable
variations, the researchers found, successfully blocked
HIV-1's ability to replicate itself in cases where the strain
of HIV had a weak version of Vif.
Unfortunately, when the HIV-1 virus had a strong version of
Vif, the protective proteins no matter how stable or potent
lost their battle to infection.
Going forward, Harris says, he and his colleagues hope to
learn ways to stop Vif from harming the APOBEC3
enzymes. "One could imagine drugs that stop Vif from
binding with APOBEC," Harris said in a press release .
Believing this to be “a bonafide HIV killing pathway,” Harris
and his co-researchers want to activate it in infected
persons. This approach might indefinitely suppress the
virus and stop it from replicating, he speculates, or it could
even result in curing HIV.
Source: Refsland EW, Hultquist JF, Luengas EM, et al.
Natural Polymorphisms in Human APOBEC3H and HIV-1 Vif
Combine to Affect Viral Infectivity and G-to-A Mutation
Levels in Primary T Lymphocytes. PLOS Genetics. 2014.