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Monkey Study Points to Gut Virome Shift During AIDS Development

NEW YORK (GenomeWeb News) – The gastrointestinal damage that's been noted in individuals with AIDS may relate, in part, to expansions of viral communities in their intestines, according to a new Cell study focused on a monkey model of the disease.

A team led by investigators at Washington University and Beth Israel Deaconess Medical Center used deep metagenomic sequencing to get a peek at the communities of viruses present in the guts of rhesus monkeys infected with simian immunodeficiency virus, or SIV, which eventually leads to AIDS in the animals.

When the researchers compared viral DNA and RNA sequences found in fecal samples from monkeys with pathogenic SIV infections to those in samples from uninfected animals or African green monkeys with non-pathogenic forms of the virus, they found monkeys with pathogenic infections had more viral sequences in their samples. Among them, sequences from known and previously undescribed viruses.

At least some of these viruses turned up in blood samples from monkeys that developed AIDS, supporting the notion that such enteric virome expansions might spur some of the widespread immune activation that accompanies AIDS development.

"We speculate that the enteric virome contributes to the progression of SIV infection to AIDS by fostering intestinal epithelial damage and systemic immune activation via release of pathogens as well as bacterial, viral, fungal, or other [pathogen-associated molecular patterns] and antigens into host tissues and the systemic circulation," Washington University researcher Herbert Virgin and Beth Israel Deaconess Medical Center's Dan Barouch, the study's co-corresponding authors, and their colleagues wrote.

If such patterns hold in humans, they noted, a clearer understanding of the enteric virome in HIV infected individuals might provide an opportunity to understand — and find markers for — disease progression.

Past studies have shown that the progression from HIV in humans or pathogenic SIV in monkeys to AIDS involves a series of steps leading to compromised immunity, the researchers explained, including systemic activation of the immune system.

In SIV-susceptible animals such as rhesus macaques, for instance, systemic immune activation appears to coincide with damage to the intestinal lining — a process that appears to allow immune antigens and pathogenic particles in the intestine to move into the blood and other parts of the body.

Researchers suspect that this intestinal damage could contribute to advanced disease by bumping up immune system activity throughout the body, based on studies of natural SIV hosts such as African green monkeys. These animals don't normally develop AIDS following SIV infection, though they do show systemic immune activation and rampant viral replication when exposed to additional antigens.

"This suggests a feed forward mechanism contributing to translocation of [pathogen-associated molecular patterns] or antigens into tissues," authors of the study explained, "which contributes to systemic immune activation, increased lentivirus replication, progressive immune deficiency, and AIDS."

To explore the role that intestinal viruses play in this process, if any, the researchers used the Roche 454 GS FLX Titanium platform to sequence viral RNA and DNA in fecal samples from uninfected rhesus monkeys and rhesus monkeys that were pathogenically infected with SIV for around four months and 16 months.

They then compared the viral communities in those animals to one another, to uninfected African green monkeys, and to African green monkeys with non-pathogenic SIV infections.

In rhesus macaques with pathogenic SIV infection, the team saw a jump in the number of viral sequences in stool samples relative to the uninfected control animals, both at the 24-month and 64-month time points.

Follow-up PCR and cell culture analyses supported the notion that viral communities differed in the uninfected and infected rhesus monkeys. Within the pathogenically infected animals, for instance, researchers detected sequences resembling a range of known viruses, along with 32 new viruses.

For a few of the monkeys with pathogenic SIV infections, they identified adenoviruses suspected of causing lesions within the intestine. And some of the parvovirus sequences found in fecal samples from SIV-infected animals also turned up in blood samples when the same monkeys developed AIDS.

In contrast, investigators did not detect enteric virome expansions in vervet and sabaeus African green monkeys that were infected with a non-pathogenic form of SIV, even after months or years of infection.

Although pathogenic SIV infection appeared to coincide with a dip in bacterial DNA sequences in fecal samples, the group's analyses did not uncover any significant shifts in bacteria at the family level.

Still, the study's authors cautioned, "analyses of possible SIV-associated changes in the bacterial microbiome and of relationships between the virome and the microbiome will … require generation of sequence libraries large enough to support analysis of the bacterial microbiome at the genus, species, and strain levels."