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Cell research uncovers intriguing clues to ’trojan horse’ gene in HIV infection

07.04.2004


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 HIV infection.

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, M.D., Ph.D., 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 Dr. Finkel. "Therefore, we urgently need new treatment approaches, including ways to prevent latent infection." The study by Dr. Finkel and her colleagues Jiyi Yin, M.D., and Maria Chen appears in the March issue of the journal AIDS.

The study builds on previous research by Dr. 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 Dr. 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 Dr. Finkel, implies that some mechanism must be protecting the infected cells from apoptosis, or programmed cell death.

Dr. 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 Dr. 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," Dr. Finkel emphasized the gene’s role in protecting HIV’s home in host cells.

Dr. 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 shanghais HALP for its own designs by promoting latency, which shields infected T cells from immune system attack, leaving them free to reproduce the virus. "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 Dr. Finkel.

Dr. 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 Dr. Finkel, "Our hope is that better understanding of how HIV acts will lead to more effective treatments for patients."

Dr. 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 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.

"Differential gene expression during HIV-1 infection analyzed by suppression subtractive hybridization." AIDS. 2004, volume 18, pages 587-596.

Founded in 1855 as the nation’s first pediatric hospital, The Children’s Hospital of Philadelphia is ranked today as the best pediatric hospital in the nation by U.S.News & World Report and Child magazine. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals and pioneering major research initiatives, Children’s Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country, ranking second in National Institutes of Health funding. In addition, its unique family-centered care and public service programs have brought the 430-bed hospital recognition as a leading advocate for children and adolescents from before birth through age 19.

Joey McCool | EurekAlert!
Further information:
http://www.chop.edu

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