Attacking persistent HIV reservoirs via a ‘long noncoding’ RNA

Electromicrograph showing an HIV-infected T cell in blue and yellow
Long noncoding RNAs, which dial protein-producing genes up or down, could be key in eradicating HIV reservoirs. (NIAID)

As effective as antiretroviral drugs have been in the treatment of HIV, the virus can still hide out in the body in reservoirs that have proven exceedingly difficult to eradicate. Now researchers at Cornell University have found a new way to attack these HIV reservoirs, and it involves “long noncoding” RNAs (lncRNAs), which don’t produce proteins themselves but instead dial protein-producing genes up or down.  

The Cornell scientists discovered that a lncRNA called SAF is dialed up in macrophage cells that harbor HIV reservoirs. When they blocked SAF in HIV-infected cells, the reservoirs self-destructed. They reported their findings in the journal Proceedings of the National Academy of Sciences.

The team started by screening 90 lncRNAs in healthy cells, HIV-infected cells, and so-called bystanders, which are cells that had been exposed to HIV but not infected. Previous studies had implicated SAF as an inhibitor of cell death, so they suspected it was keeping HIV-infected cells alive.

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After the screen confirmed their suspicion, they wanted to demonstrate SAF's activity in HIV. So they silenced the RNA in all three populations of cells. All of the HIV-infected cells died, while the healthy and bystander cells were left standing.

"We were all surprised by the specificity of the cell death," said co-author David Russell, Ph.D., professor of infection biology at Cornell University College of Veterinary Medicine, in a statement. "This showed us that when cells are infected with HIV, the virus alters the long non-coding RNAs' expression in that cell."

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HIV researchers have made strides of late in their efforts to combat HIV reservoirs. Last September, a group at the University of North Carolina at Chapel Hill reported progress in their efforts to remove T cells from HIV patients and infuse them back into the body along with drugs to make latent HIV reservoirs more visible to the immune system. And the Fred Hutchinson Cancer Research Center is investigating the potential of gene-edited stem cells taken from patients’ bone marrow in eradicating HIV reservoirs.

The next step for the Cornell team is to screen for drugs that can prompt HIV-infected cells to self-destruct. They’ll start by looking for SAF inhibitors, Russell said, but they also plan to investigate other mechanisms for clearing HIV reservoirs.

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