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HIV-1’s high virulence might be an accident of evolution

Posted by pozlife on June 20, 2006

The virulence characteristic of HIV-1–the virus predominantly
responsible for human AIDS–might amount to an accident of evolution,
new evidence reveals. A gene function lost during the course of viral
evolution predisposed HIV-1 to spur the fatal immune system failures
that are the hallmarks of AIDS, researchers report in the June 16, 2006
Cell.

AIDS has killed more than 25 million people since it was first
recognized in 1981, according to The Joint United Nations Programme on
HIV and AIDS. In 2005, an estimated 4.1 million were newly infected
with the virus. While infection with related strains of “simian
immunodeficiency virus” (SIV) is similarly rampant among many species
of monkeys, naturally infected nonhuman primates usually don’t suffer
the symptoms associated with AIDS. The evidence now revealed by an
international team of researchers is the first to offer an explanation
for this striking difference.

The group found that a viral protein earlier shown 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 viral Nef protein
ratchets down the activation of critical agents of immunity called T
cells following SIV infection, thereby limiting the detrimental effects
otherwise caused by chronically strong immune activation.

The HIV-1 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 full-blown AIDS, reports Frank Kirchhoff of the
University of Ulm in Germany and his colleagues.

“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,” the
researchers 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.”

“Heightened immune activation is the only clear cut difference
between pathogenic and non-pathogenic infections with the
immunodeficiency viruses,” 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.”

Study coauthor 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. 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.

Of more than 30 SIVs that have been molecularly characterized,
all encode a Nef gene. However, Kirchhoff noted, functional information
about the gene’s role had been almost exclusively derived from the
HIV-1 version of Nef. To get a broader evolutionary perspective in the
current study, Kirchhoff’s group examined nef gene variants taken from
a variety of divergent SIV lineages.

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, the researchers found. In
contrast, they report, the nef gene of HIV-1 and a subset of closely
related SIVs failed to limit T cell activation and death.

“Intriguingly, 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
Paul Sharp, of the University of Nottingham, who is a leading expert in
HIV and SIV evolution.

“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,” 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, Kirchhoff said. Rhesus macaques infected with
the mutant virus had extremely low viral loads and “either no
pathogenicity, or a markedly protracted disease course.” Similarly,
humans infected with nef-defective HIV-1 progress to disease symptoms
slowly, if at all.

Several Nef functions were found to be likely contributors to
the effect, including the gene’s ability to get around the immune
system.

“The gene was shown to be important for viral pathogenicity,”
Kirchhoff said. “It appeared that Nef was a ‘bad guy’ because it
enhanced persistence and replication of the virus.”

The new findings suggest the gene’s role may be less black and
white. “SIV Nef not only facilitates SIV persistence but may act as a
‘rheostat,’ allowing high enough levels of T cell activation to ensure
sufficient viral replication and transmission, while at the same time
preventing escalation of immune activation to levels that may be
harmful to the host,” the researchers said.

The results also raise the possibility that treatments that
could carefully limit the immune system in infected humans–mimicking
the tight balance maintained in the other primates–might offer a new
approach to HIV therapy, Kirchhoff said.

“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,” he said. “If you could somehow dampen the response, it
might effectively convert the condition to the more chronic,
asymptomatic infection seen in monkeys.”

Further studies by the team will examine whether SIVs carrying
Nef genes artificially made incapable of limiting T cell activation
might become more pathogenic in their natural monkey hosts. The group
will also examine whether Nef variation among HIV-2 strains might
explain differences in the rate of progression to disease in infected
humans.

###

The researchers include Michael Schindler, Jan Münch, and Frank
Kirchhoff of the University of Ulm in Ulm, Germany; Olaf Kutsch, Hui
Li, Mario L. Santiago, Frederic Bibollet-Ruche, and Beatrice H. Hahn of
the University of Alabama at Birmingham in Birmingham, AL; Michaela C.
Müller-Trutwin of Institut Pasteur in Paris, France; Francis J.
Novembre of Emory University in Atlanta, GA; Martine Peeters and
Valerie Courgnaud of University of Montpellier in Montpellier, France;
Elizabeth Bailes and Paul M. Sharp of University of Nottingham, Queens
Medical Centre in Nottingham, UK; Pierre Roques of CIRMF in
Franceville, Gabon; Donald L. Sodora of University of Texas
Southwestern Medical Center in Dallas, TX; Guido Silvestri of Emory
University in Atlanta, GA and University of Pennsylvania in
Philadelphia, PA.

This work was supported by grants from the National Institutes
of Health (R12 AI 55380, RO1 AI 058718, RO1 AI 50529, R01 AI-052775,
R01 AI-066998, N01 AI 85338, P30 AI 27767, P30 CA 13148, P51 RR-00165,
UO1 AI-067854), the Bristol Myers Freedom to Discover Award, the
Deutsche Forschungsgemeinschaft, and the Wilhelm-Sander-Stiftung.

Schindler et al.: “Nef-Mediated Suppression of T Cell
Activation Was Lost in a Lentiviral Lineage that Gave Rise to HIV-1.”
Publishing in Cell 125, 1055–1067, June 16, 2006. www.cell.com

Preview by Foster et al.: “HIV Pathogenesis: Nef Loses Control.”

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