If
left untreated, HIV will
typically progress to AIDS; that is the general rule. However, a small subset
of HIV-positive people is believed to be able to control HIV without ever
progressing to AIDS—and
without the use of antiretroviral drugs. These people, once called long-term
non-progressors, are today commonly referred to as HIV
elite controllers.
While
experts had long considered this level of innate resistance a mystery, the bulk
of evidence today suggests that specific genetic mutations confer to this
"elite" control of HIV. As such, greater focus is being placed on
determining if the same mechanisms can be mimicked in other people, with the aim
of designing an AIDS
vaccine or some immunologic approach to controlling HIV
drug without the use of drugs.
Elite Controllers
Elite
controllers are broadly defined as HIV-positive people who maintain an
undetectable HIV viral loads without the use of HIV drugs. Relieved
of the burden of uncontrolled viral activity, elite controllers typically have
well-preserved immune systems (as measured by the CD4 count), meaning
their risk of opportunistic
infection is considered low.
It
is estimated that elite controllers account for about 1 in 300 HIV-infected
people. That figure can vary, however, given that research often defines elite
controllers differently.
In
some cases, elite controllers are defined as being able to maintain
undetectable virus for a year; others are only included after anywhere from
3-15 years.
This
is an important distinction because we cannot confidently say those elite
controllers will never advance in their disease or experience a
sudden activation of viral activity.
We
must assume that some of this population will.
Mechanism of Elite Control
Early
studies were not successful in finding common traits and characteristics among
elite controllers. It was not until the advent of genetic
research and technologies that we were able to pinpoint commonalities among
those with presumed elite control.
Among
the key researchers, Harvard Medical School scientist Bruce Walker, M.D. was
among the first to isolate the genetic differences in the make-up of this
population, drawing evidence from a cohort of 1,100 elite controllers and 800
people with AIDS.
In
the normal immune
system, specialized immune cells, called "helper" T-cells,
recognize disease-causing viruses and "tag" them for
neutralization. "Killer" T-cells then lock onto the virus
at specific attachment points and effectively kill the virus from within.
However,
HIV can adapt to the immune
onslaught, mutating to prevent the "killer" cell attachment, while
destroying the "helper" cells needed to signal the attack in the
first place.
In
his group's research, Walker was able to determine that the "killer"
T-cells in the elite control group were able to function independently of
"helper" T-cells.
Furthermore,
his team found that the "killer" cells were able to neutralize a
broad diversity of HIV, not
just a specific subset as is most often the case.
Since
Walker's research was published, scientists have been able to isolate many of
the genetic
mutations found in the genome of the elite control population. Among them:
- The mutation of the FUT2 gene, which is found in 20% of the European population and is known to provide strong resistance to other types of virus.
- The presence of specialized genes called human leukocyte antigen B (HLA-B), which are found in a large proportion of elite controllers.
The
genetic mechanism which allows elite controllers to produce so-called broadly
neutralizing antibodies (bNAbs) faster than non-elite
controllers. bNAbs, by definition, can kill a broader variety of HIV.
Typically, a non-elite-controller can take years to produce these cells, by
which time HIV
has already establish hidden latent reservoirs which are largely
impenetrable to attack. Elite controllers, by contrast, seem to be able to
activate bNAbs almost immediately, preventing (or at least reducing) the
establishment of latent reservoirs.
By
identifying these genetic mechanisms, scientists hope to replicate the
processes either through gene therapy, an immunologic vaccine, or a combination
of biomedical approaches.
Downside to Elite Control
Despite
the optimism surrounding elite control and associated vaccine research,
increasing evidence has shown that elite control comes at a price. When
compared to non-elite-controllers on antiretroviral
therapy (ART), elite controllers tend to have more than twice the number of
hospitalizations, particularly from non-HIV-associated diseases that are known
to disproportionately affect all people with HIV.
When
compared to non-elite-controllers on ART
with undetectable viral loads, elite controllers had 77% more hospitalizations.
Even non-elite-controllers with detectable virus fared better, suggesting that
ART manages to minimize some of the long-term chronic inflammation that we know
can increase the risk and premature development of non-HIV-associated cancers,
cardiovascular diseases, and neurological disorders.
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