How Does the Microbiome Impact HIV Risk and Treatment?
The microbiome is a collection of trillions of organisms living within the human body. Although bacteria, viruses, and fungi are typically associated with dangerous infections, in recent years scientists have uncovered an entire universe of apparently beneficial microorganisms that help people digest their food, clean their skin, and even interact with their immune system.
The microbiome is "absolutely required for the development of the mucosal immune system," said Colleen Kelley, M.D., M.P.H., associate professor of medicine in the Division of Infectious Diseases with Emory University in Decatur, Georgia. "The microbiome is itself an organ -- it has its own metabolic activity."
The microorganisms living within people tend to band together to form small communities in different regions of the body, akin to neighboring countries with distinct cultures. Scientists have identified different microbial communities living in the gut, anus, and vagina -- three regions where microbes might come face-to-face with HIV.
In fact, the vaginal, anal, and gut microbiome regions are now the focus of intense scientific research, according to presentations by Kelley and others at IDWeek 2018 in San Francisco. Much of the current frenzy of microbiome research in HIV was inspired by studies that found women with bacterial vaginosis (BV) are more likely to acquire HIV.
Recently, researchers also found that the composition of the vaginal microbiome can impact the effectiveness of topical HIV prevention medications. That was a wake-up call for those working in HIV treatment and prevention, because it implied that we may need to customize treatment efforts to correlate with each person's unique microbiome.
"By now, several studies have linked BV with increased risk of HIV infection," said Sujatha Srinivasan, Ph.D., with the Vaccine and Infectious Disease Division at the Fred Hutchinson Cancer Research Center in Seattle.
Now, researchers are asking whether particular bacterial communities -- or specific vaginal bacteria -- are associated with increased risk. Much of the pioneering work in this area was led by Douglas Kwon, M.D., Ph.D., and his lab at Harvard, Srinivasan said.
By studying HIV acquisition in African women, Kwon and his colleagues found that women with diverse, heterogeneous microbiome communities dominated by anaerobes other than Gardnerella vaginalis had a four-fold increased risk for HIV acquisition.
Srinivasan presented her research, published in January 2018 in The Lancet Infectious Diseases, which evaluated a much larger cohort of women. That study also found that vaginal bacterial community diversity correlated with higher risk of HIV infection. When appearing in high concentrations, seven specific types of microbiota were correlated with a greater risk of infection. Those seven types were Parvimonas species type 1 and type 2, Gemella asaccharolytica, Mycoplasma hominis, Leptotrichia/Sneathia, Eggerthella species type 1, and vaginal Megasphaera species.
According to Kelley, research in the vaginal microbiome created important new questions about how HIV might interact with the rectal microbiome.
"We know very clearly, and we've known for a very long time, that sex causes shifts in the vaginal microbiome in women," she said. "So does it cause shifts in the rectal mucosa in men who have sex with men? One way to measure that is looking first at diversity."
According to research by Kelley's team that was published online in March in AIDS Research and Human Retroviruses, there doesn't seem to be a difference in the number of shared microbiota species between men who have sex with men (MSM) having condomless sex and men who are not having anal sex.
"This is because ... men who have sex with men and [the control group] -- both have objective healthy microbiota," she said. "It's not until you get within bacterial phyla that you start to see differences."
"Over time, the rectal microbiota of men who have sex with men shifts to favor enrichment of Prevotella, [a] genus of Gram-negative bacteria that's also present in the gut and been associated with HIV infection," Kelley said.
"The main take-home point is the enrichment of Prevotella," said Kelley. She added that this effect "has been seen in other cohorts in MSM in Europe, so this is not an effect of diet or environmental exposure, as far as we can tell."
Kelley and her colleagues also examined what effect lubricants -- often used by MSM during anal sex -- might have on the rectal microbiome. Lubricants are known to cause mucosal injury, and prior to the study, Kelley hypothesized that repeated mucosal injuries create a microbiome environment that's better able to metabolize products of the injury.
If true, that would cause the composition of the microbiome to shift away from a genus of bacteria called Bacteroides and toward Prevotella.
In fact, her study, called the PrEP Lube study, found a decrease in the abundance of Bacteroides genus and a trend toward increased abundance of Prevotella in men who use lube, Kelley said.
"Prevotella has historically been associated with HIV infection, and I think that this study as well as other studies in the literature really question whether Prevotella is a pathologic species," Kelley said. "I think it's probably just a marker of something that's going on at the mucosal surface."
HIV also interacts with the microbiome in the gut, where initial infection prompts an inflammatory response.
"During the chronic phase of the infection, you get inappropriate interactions between the microbiome and the immune system," said Jason Brenchley, Ph.D., of the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland.
Brenchley and his colleagues are hoping to learn more about why people with HIV are more likely to die of cardiovascular disease and other comorbid conditions, and they think the answer may lie in the role the gut microbiome plays in the body's inflammatory response to the initial HIV infection.
They use primates infected with simian immunodeficiency virus (SIV) in their research. In a recent study, they split the animals into two study arms -- half treated with antiretroviral medicine, and the other half treated with antiretrovirals plus probiotics to enhance their gut microbiota.
"The animals that had ARVs and probiotics never had a clinical event," Brenchley said. "We do think the probiotics was imparting some sort of benefit."
Brenchley cautioned that much more research is needed to understand which probiotics work best in humans living with HIV, but these early findings could one day lead to an optimized medication regimen that will help people with HIV live longer lives.