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Study Finds Non-Integrated HIV Silenced By Chromatin Modifications

NEW YORK (GenomeWeb News) – Reverse-transcribed HIV that isn't integrated into the host genome is kept silent by chromatin modifications that can be altered by fatty acids similar to those produced by gut bacteria, according to a new study.

Using chromatin immunoprecipitation and other molecular approaches, researchers from the University of North Carolina found evidence that the DNA from reverse-transcribed HIV-1 that isn't integrated into host genomes has a chromatin structure and modifications that inhibit HIV-1 gene transcription — silencing that's lost following exposure to the histone deacetylase inhibiting compounds or some short chain fatty acids they tested.

The research, scheduled to appear online this week in the Proceedings of the National Academy of Sciences, suggests non-integrated viruses may play a previously under-appreciated role in HIV infection.

The RNA genome of HIV is reverse-transcribed to DNA and integrated into the host genome using an enzyme called integrase. But only about five percent to 30 percent of these reverse-transcribed viruses are incorporated into the host's genetic code, senior author Tal Kafri, a microbiology and immunology researcher at the University of North Carolina at Chapel Hill, told GenomeWeb Daily News.

The non-integrated HIV sequences, called episomal HIV, linger in the nucleus as either linear or circular DNA. Although previous studies have detected some transcription from these viruses in the past, this episomal HIV is still poorly characterized, Kafri explained.

He and his team used chromatin immunoprecipitation to assess episomal HIV from a human cell lines transfected with either integrase-efficient HIV-1 or HIV-1 vector particles or deficient versions lacking the enzyme for integrating into the host genome.

The researchers' results suggest that both the integrated and non-integrated HIV particles are organized into chromatin-like structures, complete with histone modifications resembling transcriptionally silent DNA in the human genome.

That's not entirely surprising, Kafri said, since past studies have found similar chromatin-like structures being formed by non-integrated DNA viruses such as SV40 and hepatitis B.

The epigenetic features of HIV-1 shifted after the cells were treated with the histone deacetylase inhibitor, or HDACi, sodium butyrate, the team reported. Three days after sodium butyrate treatment, they detected a roughly seven-fold jump in the expression of the episomal HIV genes.

This increase in gene expression coincided with elevated H3 and H4 acetylation and H3-K4 dimethylation.

The team found similar results when they treated episomal HIV particle-containing cells with other small chain fatty acids or spent media from bacterial cultures.

Nevertheless, the researchers found that the ability to overcome transcriptional silencing using these compounds diminished over time. Two weeks after sodium butyrate treatment, they detected similar histone modifications without accompanying gene expression changes, Kafri said, suggesting epigenetic modifications that silence HIV gene expression may be augmented over time.

Based on these findings, Kafri said he and his team believe nucleosome formation and histone modifications of episomal HIV represent a cellular defense against the virus that may also be active against integrated versions of the virus.

"We believe that integrated HIV undergoes the same kind of silencing," Kafri said. "The host tries to protect itself from transcription of viral genes."

Because the fatty acids used in the paper resemble those produced by bacteria residing in the human gut, the researchers are currently exploring the possibility that these compounds influence HIV gene expression.

"There is the potential that there will be some kind of [HIV] reservoir," Kafri noted. "I think it's something we need to take into consideration, especially in early stages of HIV infection."

The team's subsequent experiments also suggested that there are interactions between integrated and non-integrated forms of HIV-1 in human cells. Together, the findings suggest that integrated forms of HIV may assist the non-integrated, episomal forms of the virus, Kafri explained.

While the episomal HIV may get diluted out of actively dividing cells, he added, non-integrated viral DNA could affect non-dividing macrophages, immune cells in the human body that engulf and destroy foreign material. Even so, Kafri said more work is needed to explore this possibility and to better understand episomal HIV-1 in general.