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Attention on inflammation also turns to fungi

HIV infection is associated with a range of complex injuries to the immune system that, if left untreated, ultimately result in life-threatening infections, certain cancers and relentless weight loss. However, in Canada and other high-income countries, the widespread availability of HIV testing and treatment (ART) has significantly reduced AIDS-related deaths. ART does this by suppressing the production of HIV by infected cells. Once the amount of HIV in the blood falls to very low levels, the immune system begins to rebuild itself. The effect of ART is so profound that doctors and scientists expect that many ART users will have near-normal life expectancy.

However, ART does not cure HIV infection, and while it usually restores a great deal of the immune system’s functions, some immunological dysfunction persists. For instance, HIV is associated with excess activation of the immune system and excess general inflammation. ART significantly reduces these effects but not back to the very low levels of immune activation and inflammation found in healthy HIV-negative people. Some scientists say that the excess inflammation and immune activation found in HIV-positive people may increase their risk of health problems in the future. For more information about these issues, see TreatmentUpdate 223.

The exact cause of the excess immune activation and inflammation in ART users is not clear. One theory is that HIV infection weakens intestines, allowing microbes (bacteria, fungi) and/or proteins associated with these microbes to leak through the gut into the blood. Once in the blood, these microbes and/or their proteins circulate and contribute to excess immune activation and inflammation. Clinical trials are underway with different potential interventions to address these issues. Until recently, scientists who conducted research on the movement of microbes and/or their proteins from the gut to the blood of HIV-positive people focused exclusively on one group of microbes—bacteria. They named the movement of bacteria and/or their proteins from the gut to the blood “microbial translocation” or “bacterial translocation.” Research on minimizing bacterial translocation continues.

Enter the fungi

Some scientists who have been working on microbial translocation have had results that directed them to look at the role of fungi in this issue. Emerging research suggests that fungi and/or fungal products in the gut likely also contribute to the excess immune activation and inflammation associated with chronic HIV infection. They have called the issue of fungi and/or fungal products moving from the gut into the blood “fungal translocation.”

A team of scientists at McGill University in Montreal has performed a series of elegant and sophisticated experiments that strongly suggest that fungal translocation occurs in the gut of HIV-positive people. Furthermore, the researchers found that when these people started ART early in the course of HIV infection, levels of fungi and/or fungal products were high. Even when these people took ART for two years, the levels of fungal translocation did not fall. Elevated levels of fungal translocation were associated with excess immune activation and inflammation.

Thanks to the work of scientists in Montreal and elsewhere on fungal translocation, teams of researchers are considering pilot studies to test potential interventions in order to try to reduce HIV-related immune activation and inflammation.

We do not report the details of the different experiments done by the scientists in Montreal, as they were complex. Instead we focus on their results and, later in this issue of TreatmentUpdate, potential interventions for fungal translocation.

Results

The scientists in Montreal focused on a substance called beta-D-glucan (BDG). This substance is found in the cell wall of fungi and can also be found in the blood and spinal fluid of people with invasive fungal infections. However, the Montreal scientists took steps to rule out the presence of invasive fungal infections so the cause of elevated BDG levels in the blood of HIV-positive people was due to fungal translocation.

Key findings

  • Levels of BDG in the blood of people with early HIV infection were higher than those found in healthy HIV-negative people.
  • High levels of BDG in HIV-positive people not taking ART were associated with low CD4+ cell counts, elevated viral load and a range of proteins linked to gut injury, inflammation and immune activation.
  • Initiation of ART early in the course of HIV infection stabilized BDG levels in the blood of participants. That is, ART prevented BDG levels from rising further, but BDG levels did not fall even after two years of ART.
  • BDG levels were not affected by age or gender.

Other research

The findings from Montreal are supported by other research. For instance, a study by the U.S. AIDS Clinical Trials Group (ACTG) found that elevated levels of BDG were associated with a statistically increased risk for non-AIDS-related events, including the following:

  • heart attack/stroke
  • cancers unrelated to HIV infection
  • serious bacterial infections
  • death unrelated to AIDS

Other studies in the U.S. have found that elevated levels of BDG in the blood are associated with heart-lung problems (such as elevated blood pressure within the lungs) and even HIV-related neurocognitive issues.

Taken together, the research from McGill and the U.S. strongly suggests that fungal translocation, as measured by BDG levels in the blood of HIV-positive people who do not have invasive fungal infections, should now become the focus for interventions.

Resource

TreatmentUpdate 223

—Sean R. Hosein

REFERENCES:

  1. Mehraj V, Ramendra R, Isnard S, et al. Circulating (1→3)-β-D-Glucan is associated with immune activation during HIV infection. Clinical Infectious Diseases. 2019; in press.
  2. Hoenigl M. Fungal translocation: A driving force behind the occurrence of non-AIDS events? Clinical Infectious Diseases. 2019; in press.
  3. Hoenigl M, Moser C, Funderburg N, et al. Soluble urokinase plasminogen activator receptor (suPAR) is predictive of non-AIDS events during antiretroviral therapy-mediated viral suppression. Clinical Infectious Diseases. 2019; in press.
  4. Ramendra R, Isnard S, Mehraj V, et al. Circulating LPS and (1→3)-β-D-Glucan: A folie à deux contributing to HIV-associated immune activation. Frontiers in Immunology. 2019 Mar 18;10:465.
  5. Weiner LD, Retuerto M, Hager CL, et al. Fungal translocation is associated with immune activation and systemic inflammation in treated HIV. AIDS Research and Human Retroviruses. 2019 May;35(5):461-472.