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While current HIV treatments can successfully manage an active infection, the virus can survive in tissue reservoirs, including macrophage cells, and remains a persistent problem. Today, Dr. David Russell, William Kaplan Professor of Infection Biology at the College of Veterinary Medicine at Cornell University, and his research team have come up with a new angle of attack that could selectively eradicate these viral reservoir cells while leaving intact healthy cells.
In their study published March 25 in the newspaper PNASRussell's team, led by Dr. Saikat Boliar, lead author and postdoctoral researcher, describes how a genetic regulator called SAF helps HIV-infected macrophages to prevent cell death. After blocking FAS in HIV-infected cells, the researchers found that these reservoir cells self-destruct. "We were all surprised by the specificity of cell death," said Russell. "Only infected cells die, while neighboring cells, exposed to the same treatment at the same dose, showed no death."
While macrophages, immune cells that absorb foreign entities into the body, are useful for fighting certain microbes, they are the perfect hole for HIV. Some researchers believe that these infected macrophages are reservoirs of persistent HIV infection. "Current anti-HIV drugs work very well in cases of active infection, but tissue reservoirs are a problem," says Russell. "These persistent virus sites are resistant to all current therapies."
Russell, Boliar and their colleagues wanted to study the cellular mechanisms involved in keeping infected macrophages alive and focused on long non-coding RNAs (lncRNAs), genetic coding elements that alter or inhibit genes. do not translate directly into the proteins themselves. "We were interested in long noncoding RNAs as they are known as" master regulators "of cellular pathways, and they had not been systematically considered in HIV infection," explains Russell .
The team examined a panel of well-defined 90 well-known human DNA RNAs in three distinct populations of human macrophages: healthy cells, HIV-infected cells and "control" cells – those that had been exposed to HIV but not infected.
Investigators found that one of the INN RNAs, called SAF, was markedly upregulated in HIV-infected macrophages. Previous studies had shown that FAS prevented apoptosis or self-destruction in cells. Russell and his team suspected FAS of protecting HIV-infected macrophages from death.
To prove this theory, the team blocked the action of SAF by using another non-coding RNA, called small interfering RNA (siRNA), that effectively degrades targeted RNAs such as SAF. Researchers silenced FAS in healthy, infected and occasional macrophage populations; HIV-infected cells suddenly self-destruct, while healthy and neighboring cells remain unharmed.
"This has shown us that when cells are infected with HIV, the virus alters the expression of long non-coding RNAs in that cell," Russell explains. This would explain why control cells that are exposed to HIV virions, but do not actually infect them, do not have the same response.
This discovery opens a new angle for the cure of HIV: the selective destruction of persistently infected cells – and the Russell team is eager to exploit it for potential therapeutic purposes.
"We plan to screen drugs for compounds that drive HIV-infected cells into programmed cell death," said Russell. The team will start by looking for inhibitors of the SAF, but also by other molecules able to effectively eradicate the cells of the reservoir through other mechanisms.
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