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June 21, 2006
HIV's Wicked Ways: An Accident of Evolution?
by Tim Horn
June 21, 1006 (AIDSmeds)—HIV's ability to damage the human immune system might
amount to an accident of evolution, notably the loss of the protective
function of a viral protein called Nef. Like HIV in humans, related
strains of simian immunodeficiency virus (SIV) are rampant among many
species of monkeys. Unlike HIV in humans, many primates infected with
SIV don't experience immune suppression or suffer the symptoms
associated with AIDS. The evidence, published by an international team
of researchers in the June 2006 issue of Cell, is the first to offer an explanation for this striking difference.
group found that a viral protein known to help the virus evade the
immune system, thereby allowing the SIVs that infect monkeys to persist
and multiply with high efficiency, also has a protective role in the
host immune system. The SIV Nef protein ratchets down the activation of
T-cells following infection in primates, thereby limiting the harmful
effects that can be caused by chronically strong immune activation.
chronically strong immune activation may seem like a good thing when it
comes to fighting HIV infection, it ends up causing the death of many
T-cells and ultimately exhausts the immune system – two factors that
can lead to AIDS.
The HIV Nef protein, and those of
its closest related simian viruses, however, lack this protective
function, leaving those infected susceptible to the heightened immune
activation associated with progression to AIDS, according to the new
"Nef-mediated suppression of T-cell
activation is a fundamental property of primate lentiviruses that
likely evolved to maintain viral persistence in the context of an
intact host immune system," Dr. Frank Kirchhoff of the University of
Ulm in Germany said. "The findings suggest that the gene function was
lost during viral evolution in a lineage that gave rise to HIV-1 and
may have predisposed the simian precursor of HIV-1 for greater
pathogenicity in humans."
activation is the only clear-cut difference between pathogenic and
non-pathogenic infections with the immunodeficiency viruses," Dr.
Kirchhoff added. "The observed difference in Nef function may provide,
for the first time, a mechanism to explain why many monkey species
naturally infected with SIV do not develop disease."
coauthor Dr. Beatrice Hahn of the University of Alabama has previously
shown that the two forms of HIV that infect humans originated from
related SIVs found in different species of African primates (see related news article).
HIV-1 – most closely related to an SIV strain found in chimpanzees – is
the more virulent of the two human strains and the source of the
majority of HIV infections throughout the world. The less pathogenic
HIV-2 evolved from a virus that infects long-tailed relatives of
baboons called sooty mangabeys. While HIV and SIV strains all infect
T-cells that are critical for a functional immune response, SIV usually
does so without causing serious damage in their natural primate hosts.
more than 30 SIVs that have been molecularly characterized, all encode
a Nef gene. However, information about the gene's function has come
from studies involving the HIV-1 version of Nef. In turn, Dr. Kirchhoff
and his group examined Nef genes taken from a variety of SIV types.
to the research conducted by Dr. Kirchhoff's group, Nef variants from
the great majority of primate SIVs, including the less virulent human
strain HIV-2, suppress the expression of a receptor normally found on
the surface of T-cells, making the immune cells less responsive to
activation. In contrast, the Nef gene of HIV-1 and a subset of closely
related SIVs failed to limit T-cell activation and death.
this loss of Nef-mediated suppression of T cell activation appears to
have occurred twice, once in the ancestor of a group of viruses
infecting Cercopithecus monkeys, and once in SIVcpz, the ancestor of
HIV-1 which infects chimpanzees," noted study coauthor Dr. Paul Sharp,
of the University of Nottingham, who is a leading expert in HIV and SIV
"What these viruses have in common is a Vpu
gene, not found in other SIVs, and so it's tempting to speculate that
the presence of Vpu is somehow causally related to the change in Nef
function," Dr. Sharp added.
The findings expand on
previous studies that found that Nef-deficient SIV failed to cause
symptoms in a monkey species normally susceptible to disease. Other
researchers have reported in the past that rhesus macaques infected
with the Nef-deficient virus had extremely low viral loads and limited
evidence of disease progression. Similarly, humans infected with
Nef-defective HIV progress to disease symptoms slowly, if at all.
altering HIV's Nef gene may not be a therapeutic possibility for those
infected with the virus, these results – along with research conducted
by several other teams – suggest the use of treatments that could
carefully limit immune system activation in humans. This, Dr. Kirchhoff
says, would mimic the tight immune system-virus balance seen in
"A strong immune response can be
good in the short term, but if sustained for a long time as in those
with HIV, it can exhaust the immune system," Dr, Kirchhoff said. "If
you could somehow dampen the response, it might effectively convert the
condition to the more chronic, asymptomatic infection seen in monkeys."