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PHILADELPHIA -- Researchers are probing details of how HIV commandeers genes in infected cells to disguise itself from the immune system. The researchers, from The Children's Hospital of Philadelphia, have identified cellular proteins expressed during HIV infection that enable HIV- infected cells to avoid apoptosis, a common cell suicide event. This survival mechanism allows the virus to maintain the infection within the compromised cells.
These findings, as yet based on studies in cells, not in patients, may
potentially lead to future treatments that could fully eliminate a patient's
Current treatments for HIV and AIDS rely on a combination of drugs called
highly active anti-retroviral therapy (HAART). "Although HAART drives down the
HIV to undetectable levels, latent (or silent) infection may surge back if the
treatment is interrupted," said the study's lead author, Terri H. Finkel,
MD, PhD, chief of rheumatology at The Children's Hospital of Philadelphia.
"Furthermore, HAART does not work for some patients, while other patients
are unable to tolerate the treatment's strong side effects," added Finkel.
"Therefore, we urgently need new treatment approaches, including ways to
prevent latent infection." The study by Finkel and her colleagues Jiyi Yin, MD, and Maria Chen appears in the March issue of the journal AIDS.
The study builds on previous research by Finkel that showed, contrary
to prevailing dogma, HIV does not always kill infected immune cells. Instead,
it kills bystander cells and somehow prevents at least some infected cells
from dying. "HIV works as both a sword and shield," said Finkel. "It
destroys some immune cells, while taking over the genetic machinery of other
immune cells and protecting itself within those cells."
Other researchers had demonstrated HIV's ability to remain latent within
normal-appearing, but infected cells despite anti-retroviral therapy. This
ability, said Finkel, implies that some mechanism must be protecting the
infected cells from apoptosis, or programmed cell death.
Finkel and colleagues used a genetic-based technique called
suppressive subtractive hybridization to identify gene products involved in
maintaining cell survival, despite HIV infection. By comparing dying T cells
with surviving T cells, the researchers identified proteins that were
associated with cell survival.
"Our evidence strongly suggests that a gene called HALP plays a crucial
role in protecting HIV-infected cells," said Finkel. The gene had been
discovered previously in humans, she added, but the current research is the
first to describe HALP's role in HIV infection. Closely related genes in mice
and rats act against apoptosis. By dubbing the gene HALP, which stands for
"HIV-associated life preserver," Finkel emphasized the gene's role in
protecting HIV's home in host cells.
Finkel suggests that if HALP interferes with apoptosis, it may play
both helpful and harmful roles. Highly similar genes in rats protect cells
when blood circulation is interrupted. HALP may similarly exert a beneficial
effect in humans during conditions of oxygen deprivation. However, it may be
that HIV usurps HALP for its own designs by promoting latency, which shields
infected T cells from immune system attack, leaving them free to reproduce the
"HIV uses host cells as a Trojan horse, a safe haven for the virus to
hide until it breaks out of latent infection to destroy other cells," said
Finkel is pursuing further investigations to establish whether HALP
indeed triggers the anti-apoptotic functions she discovered in the current
study. By shedding light on additional genetic culprits in HIV infection, her
studies may provide clues to new treatments. Future drugs could target the
proteins that help HIV survive. Many steps, and years of work, separate this
knowledge from the development of actual therapies, but, said Finkel, "Our
hope is that better understanding of how HIV acts will lead to more effective
treatments for patients."
Finkel holds a faculty appointment at the University of Pennsylvania
School of Medicine. Her co-authors on the paper are Jiyi Yin, of Children's
Hospital's Division of Rheumatology, and Maria F. Chen, of the University of
Pennsylvania Department of Cell and Molecular Biology.
Providing support for this study were the National Institutes of Health,
the University of Pennsylvania Center for AIDS Research and Cancer Center, the
Bender Foundation, the Joseph Lee Hollander Chair at The Children's Hospital
of Philadelphia, and the W.W. Smith Charitable Trust.
Source: The Children's Hospital of Philadelphia