Gut microbes help bolster immunity in people living with HIV – and, one day, these microbes may be harnessed to protect this population from infections driven by immune deficiency.
This is according to a study – “Human immunodeficiency virus-associated gut microbiome impacts systemic immunodeficiency and susceptibility to opportunistic gut infection” by Eran Elinav, Hila Elinav, Stavros Bashiardes, Melina Heinemann, Lorenz Adlung, et al – that was published in Nature Microbiology.
Tracking the microbiome over the course of HIV
The researchers analyzed the composition of the gut microbiome in the stool of about 70 people living with HIV in Israel and a similar number in Ethiopia, collecting samples from each at several time points over the course of the viral infection. For both countries, they compared the participants’ microbiomes to those of uninfected controls from the same geographical area. All HIV-positive participants received the standard antiviral therapy available in their country, though in Ethiopia the drugs tended to be less advanced than those available in Israel.
In addition to profiling the microbiome, the scientists measured levels of CD4 T cells – a central type of immune cell – in all the participants. HIV gradually destroys these cells and, if it is left untreated, the CD4 count eventually plunges, opening the door to infections and other illnesses associated with AIDS. Much of this destruction occurs in the inner lining of the gut, which houses huge numbers of immune cells. That same gut lining also serves as a major hideout for HIV, allowing the virus to lurk and survive in the intestines even when it becomes undetectable in the blood thanks to antiviral cocktails.
The microbiomes of people living with HIV were found to differ from those of uninfected controls. Moreover, the scientists noted that the mix of gut microbes – and the way the microbial populations functioned – continued to change with the progression of the infection, in ways unrelated to the viral therapy: Dozens of bacterial strains disappeared, while others gained ground.
These changes became more marked as the levels of CD4 dropped and immune deficiency intensified. Some of these microbial shifts appeared in both Ethiopian and Israeli participants, suggesting universal biological rules; others were unique to one country, probably reflecting the impact of local diet and lifestyle on the resident gut microbes.
“We believe the virus is not affecting the bacteria directly,” Eran Elinav says. “Instead, HIV affects the immune system, which normally secretes natural antibiotic molecules, and these antimicrobial peptides determine which bacteria can thrive in the gut. When the immune system is attacked by the virus, the composition of antimicrobial peptides changes, and so does the microbiome – some microbes are suppressed while others flourish.”
The researchers found that the decline in CD4 counts occurs in parallel with changes in the gut microbiome – in other words, that HIV infection may affect the microbiome through destroying parts of the immune system. But they then wondered whether the reverse is also true, that is, whether the gut microbiome affects the course of the infection – or, more precisely, the immune mechanisms related to the infection.
“It’s known among physicians that the gut serves as a kind of reservoir for HIV, and T cells in its lining remain damaged even when the immune system in the rest of the body recovers as a result of antiviral therapy,” Hila Elinav says. “In this respect, examining the role of microbiome in immunity during HIV infection was particularly important.”
When the microbiome fights back
To test the effect of the HIV-related microbiome on the immune system, the researchers transferred gut microbes from people living with HIV and from uninfected volunteers into mice that either had no microbes at all or whose microbiome had been greatly reduced by antibiotics. Since mice are not susceptible to HIV, any immune changes in these animals must have come from the mix of microbes, rather than being directly caused by the virus.
The results at first stumped the researchers: Microbiomes from HIV carriers raised the levels of CD4 T cells in the mouse intestines even higher than in mice that received gut microbes from uninfected donors. This experimental transfer allowed the researchers, for the first time in humans, to move beyond correlation and demonstrate a causal role for the microbiome in shaping immune function during HIV infection.
This striking finding suggests that in the early stages of infection, the microbiome partly compensates for the immune damage caused by HIV by increasing the dwindling T cell population in the gut. However, this was not the case for some of the participants who had progressed to severe immune deficiency and AIDS. Their microbiomes no longer provided support to the immune system. Mice that received gut bacteria from these AIDS patients had low CD4 levels; the “helping hand” of the microbiome was gone.
Finally, the researchers asked whether the marked microbial boost to CD4 T cells offers protection against infections that threaten people with HIV-related immune deficiency. In mice that received microbiomes from people with HIV, higher CD4 levels in the gut indeed translated into better clearance of the parasite that causes cryptosporidiosis, one of the classic AIDS-defining illnesses. Mice colonized with microbes from people with AIDS fared less well. This showed that the microbiome can bolster gut immune cells and reduce the risk of gut infections that take advantage of a weakened immune system – but only where HIV has not advanced too far.
The conclusion emerging from these findings is twofold. “As far as basic science goes, our study provides strong evidence in humans that the microbiome and the immune system causally affect one other,” Eran Elinav says. “In fact, the microbiome acts as a kind of an immune organ – it both shapes and responds to immunity.”
In terms of clinical significance, the findings may be relevant to people living with HIV because the microbiome can, in principle, be modified – through diet, precisely tailored probiotics, microbial metabolites or even bacteriophages that selectively kill certain bacteria. “Much work remains to identify the exact microbes and molecules involved,” says Hila Elinav. “But our study suggests that, in the future, altering the microbiome might help support immunity – and lower the risk of life-threatening infections – in people living with HIV. This would be especially critical in places where advanced antiviral therapies are still out of reach, or in patients whose immune systems are not sufficiently restored by antiviral treatment.”
