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Microbiome-based stratification of individuals at risk of HIV-1 acquisition, chronic clinical complications,antimicrobial drug resistance,and unresponsiveness to therapeutic HIV-1 vaccination

Periodic Reporting for period 1 - MISTRAL (Microbiome-based stratification of individuals at risk of HIV-1 acquisition, chronic clinical complications,antimicrobial drug resistance,and unresponsiveness to therapeutic HIV-1 vaccination)

Reporting period: 2020-01-01 to 2021-06-30

The microbiome comprises all genetic material within microbiota, the set of microorganisms living in specific niches, one of which is the human gut. It has been shown that the microbiome plays an important role in the functioning of the immune system, so microbiome disturbance may cause immune disorders and chronic inflammation. Those conditions are hallmarks of HIV infection, yet few publications have addressed the potential role of the microbiome in HIV/AIDS. The focus of the EU-funded MISTRAL project is the relationship between the gut microbiota and HIV/AIDS, specifically HIV-1. MISTRAL ultimately aims to identify biomarkers to underpin the development of interventions that mitigate HIV infection and that enhance response to vaccines and therapies. The MISTRAL project will include an open-access database to support inpatient screening and stratification and a cloud-based tool to facilitate microbiome interpretation in research and clinical settings.

In MISTRAL, we address the following 5 questions:

1. In whom do HIV vaccines work? HIV vaccine prototypes do not have the same effect on everyone. Some people generate a strong immune response against the virus, whereas in others the vaccine is not effective. The microbiome, the huge ecosystem of microbes that colonize our body, might be partly responsible for this. Many questions arise from this hypothesis; which composition of microbes improves the vaccine responses? Or vice versa, what pattern of microbes could hinder this response?

2. Can we improve HIV vaccine responses with bacteria? Preliminary data suggest that, at least in mice, gut microbiome modulation might be able to modify immune responses to HIV vaccines. Much more work is needed to identify which microbes boost and which ones refrain immune responses. MISTRAL seeks to identify microbes and molecules that could be used to improve vaccine responses. Findings in the HIV vaccine could quickly translate into other vaccines with low immunogenicity, having a huge impact on humanity.

3. Who will develop HIV clinical complications? During HIV infection, the virus depletes our body from immune cells, reducing our ability to counteract infections. Moreover, the immune system becomes dysregulated and is constantly trying to eliminate the virus, producing chronic inflammation, which leads to accelerated aging. These two facts are key for the development of clinical complications and might be influenced by the microbiome. We want to identify specific microbiome patterns that would predict who is at higher risk of developing clinical complications in order to prevent or avoid them.

4. Detecting antibiotic-resistance bacteria. The number of antibiotic-resistant bacteria is increasing, a public health problem that is alarming the scientific community. The MISTRAL project will have in its hands a huge amount of different bacterial antibiotic resistance genes, which conform to the resistome. We will evaluate how the bacterial resistome changes in different degrees of immune suppression, and how it can be modified by improving the patient’s immune system.

5. New computer tools for easy microbiome characterization. The MISTRAL project will collect information on the microbiome of hundreds of people with thousands of microbes with millions of genes. Nowadays, bringing this knowledge into the clinic requires the analysis of huge amounts of data using the latest technologies and big data approaches, techniques that are not available in every lab. Our aim is to wrap all this information and procedures and turn them into a robust yet easy-to-use software tool called ENTHERA. This tool will simplify 5 years of work into a single program that every hospital, doctor, or laboratory will be able to use. Click the button and… Magic!
The MISTRAL team has completed 3 different randomized clinical trials which are currently being analyzed. They will provide important clues as to whether the gut microbiome composition and function is associated with the ability of an HIV vaccine no boost the immune system to fight HIV. Also, they will answer if two specific probiotic and prebiotic compounds are able to ameliorate HIV-associated inflammation, as well as whether the microbiome is related to better immune recovery after antiretroviral treatment initiation. Mouse studies have begun to analyze the effects of suppressing the gut microbes on HIV vaccines and will enable addressing the effect of immune-modulating microbial compounds on HIV vaccine responses. We have also designed a cohort to identify gut microbes associated with protection from HIV infection and HIV progression in men who have sex with men, and a European-wide prospective cohort to assess clinical complications of HIV infection. Finally, MISTRAL has advanced in the development of the first prototype of a cloud-based, automated, streamlined, and user-friendly microbiome analysis. With further refinement and incorporation of MISTRAl-derived study data, such software will allow clinicians and clinical researchers to perform fast and robust complex microbiome analyses and interpretations without the need for advanced bioinformatics expertise. This should accelerate the integration of microbiome data into future clinical trials.
By the end of the project, we hope to have generated several important advances beyond the state-of-the-art with high societal impact:
If we are successful, we will discover novel strategies to minimize HIV-1 acquisition, which could benefit millions of people at risk of becoming infected with HIV worldwide. The Discovery of intestinal bacteria able to interfere with HIV-1 infection and replication could be translated into novel probiotic-based microbicides or into novel antiretroviral molecules. We aim to be able to show that the efficacy of therapeutic HIV-1 vaccines (and thus HIV cure strategies) can be boosted through specific, rationally-designed bacterial consortia. We will hopefully identify novel biomarkers associated with the development of severe non-AIDS-related complications in HIV-1 infected subjects. We will then embed the most important of such markers in Enthera, web-based software that will facilitate patient stratification for clinical decision-making and research purposes. Establishing the proof-of-concept that the immunogenicity of therapeutic vaccines can be modulated through microbiome-based interventions will revolutionize HIV cure research and will lead to multiple additional clinical trials.
The availability of novel diagnostics and new interventions may have a major impact on the organizational models of clinical care in public and private medical practice. It is important to note that microbiome testing integration in such models would represent a true example of precision medicine, not only because treatment could be tailored to each patient, but also because the microbiome can be modified and assessed in a regular fashion using non-invasive approaches.
The development of more precise genotypic-to-phenotypic AMR correlates will bring microbiome-based drug resistance profiling closer to the clinical microbiology routine and will foster the use of genotypic methods to identify, characterize and track bacterial infection outbreaks, enabling an integrated veterinary / industrial/medical approach to protect Europe from bacterial infections.
Mistral web project