Soon after exposure HIV infects immune cells in the gut, causing a drop in CD4 T-cells in the intestinal mucosa. As this barrier is damaged, bacteria in the intestines can leak out and trigger a whole-body inflammatory response, which is thought to contribute to disease progression even in people with well-suppressed viral load on antiretroviral therapy.

Using SIV -- a virus related to HIV that infects monkeys -- Lauren Hirao and Satya Dandekarfrom the University of California at Davis and colleagues looked at the earliest host-virus interactions and mechanisms of inflammation and dysfunction in the gut, even before CD4 cell depletion.

At 2.5 days after infection, while blood viral load was still low and gut CD4 cell loss had not yet occurred, they saw disruption of the gut epithelium and significant induction of IL-1β expression by Paneth cells (a type of gut epithelial cell) located near the SIV-infected cells, which triggered damage to the gut lining.

"Our study highlights the importance of the gut epithelium in HIV infection, not just as a target of pathogenesis but also the initiator of immune responses to viral infection, which can be strongly influenced by commensal bacteria," the authors wrote.

Below is an edited excerpt from a University of California at Davis press release describing the research in more detail.

The Early Cost of HIV

Inflammatory response breaks down intestinal lining, but help may come from friendly bacteria

Sacramento, CA -- August 29, 2014 -- Researchers at UC Davis have made some surprising discoveries about the body’s initial responses to HIV infection. Studying simian immunodeficiency virus (SIV), the team found that specialized cells in the intestine called Paneth cells are early responders to viral invasion and are the source of gut inflammation by producing a cytokine called interleukin-1 beta (IL-1β).

Though aimed at the presence of virus, IL-1β causes breakdown of the gut epithelium that provides a barrier to protect the body against pathogens. Importantly, this occurs prior to the wide spread viral infection and immune cell killing. But in an interesting twist, a beneficial bacterium, Lactobacillus plantarum, helps mitigate the virus-induced inflammatory response and protects gut epithelial barrier. The study was published in the journal PLoS Pathogens.

One of the biggest obstacles to complete viral eradication and immune recovery is the stable HIV reservoir in the gut. There is very little information about the early viral invasion and the establishment of the gut reservoir. 

"We want to understand what enables the virus to invade the gut, cause inflammation and kill the immune cells," said Satya Dandekar, lead author of the study and chair of the Department of Medical Microbiology and Immunology at UC Davis.

"Our study has identified Paneth cells as initial virus sensors in the gut that may induce early gut inflammation, cause tissue damage and help spread the viral infection. Our findings provide potential targets and new biomarkers for intervening or blocking early spread of viral infection," she said.

In the study, the researchers detected a very small number of SIV infected cells in the gut within initial 2.5 days of viral infection; however, the inflammatory response to the virus was playing havoc with the gut lining. IL-1β was reducing the production of tight-junction proteins, which are crucial to making the intestinal barrier impermeable to pathogens. As a result, the normally cohesive barrier was breaking down.

Digging deeper, the researchers found the inflammatory response through IL-1β production was initiated in Paneth cells, which are known to protect the intestinal stem cells to replenish the epithelial lining. This is the first report of Paneth cell sensing of SIV infection and IL-1β production that links to gut epithelial damage during early viral invasion. In turn, the epithelial breakdown underscores that there’s more to the immune response than immune cells.

"The epithelium is more than a physical barrier," said first author Lauren Hirao. "It’s providing support to immune cells in their defense against viruses and bacteria."

The researchers found that addition of a specific probiotic strain, Lactobacillus plantarum, to the gut reversed the damage by rapidly reducing IL-1β, resolving inflammation, and accelerating repair within hours. The study points to interesting possibilities of harnessing synergistic host-microbe interactions to intervene early viral spread and gut inflammation and to mitigate intestinal complications associated with HIV infection.

"Understanding the players in the immune response will be important to develop new therapies,” said Hirao. “Seeing how these events play out can help us find the most opportune moments to intervene."

9/4/14

Reference

LA Hirao, I Grishina, O Bourry, S Dandekar, et al. Early Mucosal Sensing of SIV Infection by Paneth Cells Induces IL-1β Production and Initiates Gut Epithelial Disruption. PLoS Pathogens 10(8):e1004311. August 28, 2014.

Other Source

University of California at Davis. The Early Cost of HIV. Press release. August 29, 2014.