HIV is a disease of the gut, a concept that’s easy to lose sight of with all the attention paid to sexual transmission and blood measurements of the virus and the CD4+ T cells it infects and kills. But the bottom line is that about two thirds of all T cells reside in the lymphoid tissue of the gut, where the virus spreads after exposure, even before it shows up in blood.
Blood, however, has been the focus of research and care because it is easy to sample and broadly represents what is going on throughout the entire body. The gut is a lot harder to access, which is why much of it remains a crudely delineated terrain that can only be examined with blunt and invasive tools. But a better understanding of the gut environment will be necessary to achieve the next level of advances in comprehending the disease and fashioning better interventions, researchers said last Wednesday at the annual Conference on Retroviruses and Opportunistic Infections in Boston. “Why do we care about the microbiome?” asked Nichole Klatt, a University of Washington (U.W.) pathobiologist, whose lab focuses on mucosal immunology. Klatt, who organized and chaired the conference session, answered her own rhetorical question, summarizing that HIV infection decreases the number and diversity of beneficial bacteria and increases those that have negative effects on the gut. “There are health consequences to dysbiosis,” she said.
One main area of investigation, dysbiosis, is a perturbation of the microbiome that allows organisms inside the gut to escape through the gut barrier wall into surrounding space and eventually enter the bloodstream. Dysbiosis is a general process where various forms of disruption involving different microbes, at locations along the roughly nine meters of the intestinal tract are likely to cause different medical problems.
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Eight days after exposing monkeys to SIV, the simian equivalent of HIV, Adam Ericsen, an immunologist at the University of Wisconsin–Madison saw “up to a 1,300-fold increase of bacteria circulating in the blood” of the animals. The temporal association—the number of bacteria increased in the blood before the SIV appeared in the blood—led him to believe that the virus first attacks CD4+ T cells that help protect the gut wall from microbial translocation. But then, as the animal's immune system began to exercise some control over the virus and gut barrier function improved, the level of bacteria in the blood declined. He suggests that modulating this activity might reduce the initial burst of inflammation that fuels HIV infection and the establishment of viral set points and the seeding of reservoirs.
Meanwhile on the Pacific Coast, Jennifer Manuzak, a U.W. immunologist, administered a probiotic called VSL#3 to uninfected monkeys to modulate a more favorable microbial ecosystem in the gut and improve immune function. She found “an increase in IgA- [immunoglobulin-] producing B cells in both the colon and the lymph nodes” as well as an increase in T helper cells in the lymph nodes.*
These and other findings suggested that it is possible to enhance the immune response in the gut and could work as a way to increase immune responses to vaccination that typically are weaker in people infected with HIV, the elderly and other persons at risk. But Manuzak cautions against expecting commercially available probiotics to deliver the same results; there is simply no data to support that belief.
Just how does HIV infection affect the human gut microbiome? The answer may depend on where you look. Jesus Luevano, a medical student at Harvard Medical School and a researcher the Ragon Institute examined bacterial communities from the gut of 145 people in Boston and 120 subjects in Uganda. He found very little difference between samples from the gut of HIV- positive and negative persons in Uganda, but a significant difference in Boston. Interestingly, the healthy HIV-negative Bostonians were the outliers, the guts of the other three groups was relatively similar; that was particularly true of untreated persons on both continents. “HIV-uninfected patients had much greater richness in their samples as well as a unique population that was primarily composed of bacteria from the phylum Fermicutes,” Luevano says. Viral load and treatment also had effects on community composition, but the number of persons in each subgroup of the study was too small to say anything more.
Fecal microbial transplantation (FMT) has gained acceptance for treating Clostridium difficile infection, a life threatening and difficult to treat dysbiosis that often is caused by heavy use of antibiotics. The procedure, which has a 90 percent success rate, transplants the fecal microbial ecosystem from a healthy person into a sick one, often using a colonoscope for inserting the material, to restore a healthy equilibrium.
Ma Somsouk, gastroenterologist from the University of California, San Francisco, hoped that an FMT might restore balance to the gut of HIV patients experiencing dysbiosis and immune activation that can lead to things like cardiovascular disease. After trying it in six patients Somsouk found there was little benefit. Luckily, the subjects experienced the same few side effects as other patients who have tried FMT. The main problem appeared to have been minimal engraftment—the transplanted organisms did not thrive and supplant the bugs that were already present and causing dysbiosis. Somsouk, however, was not surprised. With C. difficile a combination of antibiotics and massive diarrhea wipes out most of the bacteria in the gut, so the transplanted organisms have little competition in colonizing the gut. Somsouk was transplanting his organisms into the microbial equivalent of Manhattan and most of them got lost in the crowd.
The next phase of the study will first “condition” patients with antibiotics to knock down the local population of bacteria, as has already taken place in trying unsuccessfully to treat C. difficile patients, Somsouk says. It is similar to how radiation and chemotherapy are used to “condition” patients for a bone marrow transplant, to improve engraftment of transplanted immune cells. Somsouk thought all along that conditioning probably would be necessary to improve the changes of engraftment but he wanted to first try the less invasive approach using no antibiotics. He hopes to begin that second study in 12 patients later this year.
*Editor's Note (3/17/16): This paragraph was edited after posting. The original incorrectly identified the probiotic, VSL#3, and the B cell, IgA.