HIV Research In an Age of Antiviral Therapy
By Jason Socrates Bardi
Sometimes you see them in the most public of placeshuge
billboards, placards on the sides of city busses, and special
advertising sections in The New York Times Magazineglossy
ads with attractive models touting the wonders of the latest
antiretroviral treatment combination for those with human
immunodeficiency virus (HIV).
The images are sometimes subtle: a family at a graduation;
a young man kickboxing or swimming; a woman with a bright
smile riding a bike. The message, however, is clear: Acquired
Immune Deficiency Syndrome (AIDS) is a treatable disease.
With drugs, life can be extended.
Perhaps that message is too clear.
The Food and Drug Administration warned drug manufacturers
last week to not go too far with their advertising claims,
noting that many of these ads do not adequately convey
that these drugs neither cure HIV infection nor reduce its
Transmission rates of HIV have increased since the advent
of the type of therapy described in those ads, especially
among the 15- to 25-year-old age cohort. This increase is
largely due to increased high-risk behaviorsunprotected
sex and intravenous drug useamong kids who may have
absorbed the message that living with the virus isnt
so bad anymore.
No current treatment has ever shown efficacy at eradicating
the disease from a patient. Nor do the treatments eliminate
the risk of passing the virus along through sexual contact
or sharing needles. HIV is a hard infection to control.
The goals of current AIDS research are still the same: finding
ways to stop the spread of the virus and enable infected individuals
to live longer.
"In 99.9 percent of infected individuals," says Immunology
Professor Donald Mosier, "the immune response ultimately fails."
Mosiers laboratory has an elegant model that they
have developed to study HIV infection in vivo. Using this
model, they can test isolates from patients at various stages
in the disease and look at how the replication and infectivity
of the virus alters with mutations to its genome.
They can also use the model to study basic viral dynamics
and to test the efficacy of vaccine and therapeutics candidates
to protect live human cells against HIV. And equally important,
they can use these models to study the basic biology of HIV
and its viral dynamics.
Viral Dynamics and Immune Failure
During the first stages of an HIV infection, the virus multiplies
rapidly in a persons lymphoid organs causing a burst
of high concentration in the bloodstream that is known as
the initial viremia. This viral burst makes a person sick
and causes an immune response as CD4+ T helper cells, which
are the primary target of HIV, respond to the infection. These
activated CD4+ T cells stimulate B cells to produce antibodies
that are specific to HIV envelope proteins, which appear in
the bloodstream a few months after initial infection and are
maintained at a certain level in the bloodstream throughout
There is also an adaptive immune response mediated by HIV-specific
cytotoxic T lymphocytes (CTL) CD8+ T cells, which learn to
recognize HIV infected CD4+ T cells. These HIV-specific CTLs
come along and kill infected cells by blasting them with perforin,
an enzyme that pokes holes in infected cells.
The CTLs also produce a molecule, interleukin2, which
activates the differentiation of na•ve cells into HIV-specific
CTLs. The levels of HIV-specific CTLs in the bloodstream increases
dramatically in the first few months of infection and are
maintained at high, steady numbers throughout most of the
Once this CTL-mediated immune response is fully on, the
immune cells continue to target and kill HIV infected cells
in the body, and a leveling off occurs where the CD4+ T-helper
cells stop declining and hold steady at a blood concentration
slightly lower than normal. The amount of virus in the bloodstream
declines and evens out as wellat the level referred
to as the set point, which is a good correlate with eventual
As the disease progresses, the levels of virus, antibody,
CTL, and T helper cells remain more or less the same for anywhere
from one to ten years or more. Clinically, this is referred
to as the asymptomatic period, and throughout this entire
period, the immune system is able to respond to challenges
of infection and continuously kill cells infected with HIV.
Eventually, though, the immune system loses its battle with
HIV, largely due to a failure of CTLs to eradicate the virus.
The CTLs ultimately fail, which leads to increased killing
of T helper cells.
"Even though there isat one timea vigorous response,
it is not sustained and effective," says Mosier. "The target
somehow induces that CTL to die."
Functioning normally, the CTLs should kill infected target
cells repeatedly, but in HIV, they are killed in the act of
killing, and this back killing has a dire effect on the immune
system. "Most virus-infected cells can't fight back, but HIV-1
infected cells can."
Exactly how this occurs is one of the basic questions that
Mosier has been asking, but regardless of the mechanism, the
effect is clear.
"Its not like the CTLs are not responding to the HIV
infection," says Mosier, "but the longer it goes on, the less
effective the response becomes."
The back killing acts as a selection in which those CTLs
that are the most potent are also the ones that are the most
fragile. The result for the immune system is that overall,
the HIV-specific CTLs become less effective at killing the
virus throughout the course of the infection.
Evidence for this can be seen under a microscope. CTLs are
normally loaded with perforin granules, which they use to
kill cells, but in chronic HIV patients the HIV-specific CTLs
have no perforin granules.
"They are functionally neutered," says Mosier. "All the
killers are killed."
Meanwhile the HIV-specific CTLs are nevertheless getting
stimulated constantly. Evidence for this can be seen in the
appearance of CD28+ markers on the cells, says Mosier, which
only appear after long-term stimulation and are not present
during primary infection. The CTLs undergo very rapid turnover
during a primary HIV infection, which is evidenced by the
telomere shorteningthe fraying of the ends of cell chromosomes
which happens each time a cell divides.
"The whole CTL mechanism gets exhausted," says Mosier.
And late in the infection, the CTLs fade away, the T helper
cells decline, and the viral levels in the bloodstream shoot
up once again.
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