A ‘switch’ to kill inactive HIV?

SAN DIEGO—After all these decades, we still lack an actual cure for the HIV infection that leads to AIDS. Antiretroviral therapy has come a long way in terms of preventing HIV infection and spread, as well as in treating HIV-infected patients to make the infection more of a manageable chronic condition and less of a death sentence. But the fact is that when antiretroviral therapy stops, or if HIV becomes resistant, the virus tends to awaken quickly and spread rapidly.

But in a move that could shift the advantage farther toward care providers and patients and away from the virus, University of California San Diego School of Medicine researchers have tapped the power of genetic sequencing to identify a principal cellular player controlling HIV reproduction in immune cells. When this player is turned off or deleted, the effect seems to be the elimination of dormant reservoirs of HIV.

In a study published online Sept. 24 in the journal mBio, Dr. Tariq Rana, a professor of pediatrics and genetics at UC San Diego School of Medicine, and colleagues reported the first genome-wide expression analysis of long noncoding RNA (lncRNA) in HIV-infected macrophages. In general, the university notes, “lncRNAs do not encode the recipe for proteins the way other RNAs do, but instead help control which genes are turned ‘on’ or ‘off’ in a cell.”

“This is one of the key switches that the HIV field has been searching for three decades to find,” said Rana. “The most exciting part of this discovery has not been seen before. By genetically modifying a long noncoding RNA, we prevent HIV recurrence in T cells and microglia upon cessation of antiretroviral treatment, suggesting that we have a potential therapeutic target to eradicate HIV and AIDS.”

As noted by UC San Diego writer Yadira Galindo in a story on the university’s website, the team described how a single lncRNA dubbed HIV-1 Enchanced LncRNA (HEAL) is elevated in people with HIV. “HEAL appears to be a recently emerged gene that regulates HIV replication in immune cells, such as macrophages, microglia and T cells,” wrote Galindo. “Using a combination of genomic, biochemical and cellular approaches, they found that silencing HEAL or removing it with CRISPR-Cas9 prevented HIV from recurring when antiretroviral treatment was stopped. Additional research to confirm these effects in animal models will be performed.”

In the paper—titled “The Long Noncoding RNA HEAL Regulates HIV-1 Replication through Epigenetic Regulation of the HIV-1 Promoter”—the authors wrote, “Despite our increased understanding of the functions of lncRNAs, their potential to develop HIV/AIDS cure strategies remains unexplored. A genome-wide analysis of lncRNAs in HIV-1-infected primary monocyte-derived macrophages (MDMs) was performed, and 1,145 differentially expressed lncRNAs were identified. An lncRNA named HIV-1-enhanced lncRNA (HEAL) is upregulated by HIV-1 infection and promotes HIV replication in T cells and macrophages. HEAL forms a complex with the RNA-binding protein FUS to enhance transcriptional coactivator p300 recruitment to the HIV promoter. Furthermore, HEAL knockdown and knockout prevent HIV-1 recrudescence in T cells and microglia upon cessation of azidothymidine treatment, suggesting HEAL as a potential therapeutic target to cure HIV-1/AIDS.”

“Our results suggest that HEAL plays a critical role in HIV pathogenesis,” Rana commented. “Further studies are needed to explain the mechanism that leads to HEAL expression after an individual is infected by HIV, but this finding could be exploited as a therapeutic target.”