Metabolomics to Investigate the Immuno-metabolism and Inflamm-aging Triggered by Viral Infections
While there has been a 23 percent decline in new HIV infections since 2010 as reported by UNAIDS, progress on the prevention of HIV (human immunodeficiency virus) transmission remains slow, with estimated new infection numbers higher than the 2020 target indicated by UNAIDS. As HIV, the virus that causes AIDS, continues to be a major global health challenge, researchers like Dr. Ujjwal Neogi, Karolinska Institute, play a vital role in unraveling the mechanisms of HIV pathogenesis and natural control mechanism that can aid for functional cure or vaccine developments.
New Solutions Needed to Unravel the Mechanisms of natural control of HIV
Dr. Neogi and his team have been using metabolomic since 2016 to examine the virologic effects of disease and understand immune metabolism in infectious disease.
“Early in my schooling, I was taught that cancer has no answer and HIV/AIDS has no vaccine. These unanswered questions fascinated me and drove me in the direction to drive development in the space. After graduation, I interned in an HIV lab in the National Institute of Immunology, India. Later during my doctoral research, I had the opportunity to work directly with patients – they further motivated me to find answers for them by focusing on HIV translational research.”
Dr. Neogi has been studying HIV since 2007 with an emphasis on the natural immune control and immune aging in the population with HIV since 2017.
A small subset of HIV-1* positive individuals control viral replication and restrain progression to AIDS for a long duration of time without receiving antiretroviral therapy. These are known as “Elite Controllers” (EC). Understanding the mechanisms that underlie the viral control in EC has attracted researchers over the years whose goal is to exploit this process for therapeutic or vaccination purposes.
Two HIV virus types exist:
- HIV–1 is pandemic and aggressive
- HIV–2 is confined mainly to West Africa and less pathogenic
However, in the past three decades, progress to understand the phenotype of EC has eluded researchers due to contradictory immunological and genomic study results. Therefore, in order to understand the underlying mechanisms which, ensure that disease progression is prevented in EC, a comprehensive analysis of clinical phenotypes coupled with genetics and biomolecular mechanisms is required. This need led the team to multi-omics technologies to identify novel biomarkers of natural immune control to support the future of vaccine strategies, therapeutics and even a cure one day.
“The addition of “omics” to a molecular term implies a comprehensive, or global, assessment of a set of molecules in the central dogma such as genome, epigenome, transcriptome, proteome, metabolome, and microbiome,” says Dr. Neogi. “However, with the advancement of the field, researchers now realized that these “omes” don’t operate in a vacuum. Instead, they interact with each other. By combining these “omes” into a set of omes called “multi-omics”, one can analyze the big complex data more efficiently to understand the disease biology and find biomarkers in a more straightforward and comprehensive way.”
Metabolomics – An important tool in a multi-omics approach
The Karolinska Institute researchers in Dr. Neogi’s lab use a multi-omics approach to in their study of People Living with HIV (PLHIV). “In the past, we did multi-omics in the conventional fashion, beginning with genomics, transcriptomics, proteomics and then metabolomics,” says Dr. Neogi. “Then we decided to flip the process on its head. We started doing metabolomics first. We found the metabolomics illuminates the mechanism of action, which then allows us to move onto more targeted approaches like proteomics and transcriptomics.”
The team’s work in metabolomics has helped them to get closest to the phenotype. “For example, we found that 40 metabolites of interest will reveal truer insights to the purpose of our study whereas with transcriptomics and genomics we get a lot of data that we don’t need,” he continued.
Metabolomics has allowed the team to save time in data mining by providing more insightful data in a study that requires less mining of irrelevant findings and by illuminating environmental influence – something that not is possible with transcriptomic data.
The learnings from their work around this infectious disease may also help to illuminate the impacts of other infectious diseases such as COVID-19.
Two Key Research Themes
Dr. Neogi’s lab is helping to understand the role of metabolic perturbation in the RNA viruses. With the use of metabolomics they can help to illuminate what the body is doing to protect itself, understand how to modulate the host to fight the pathogen and pave the way for a new field of host targeted therapy.
Specifically, the group’s research can be classified into two key themes:
- Theme 1: Immuno-metabolism and aging in HIV– Understanding the dysregulated immune-metabolic profile in HIV-infected individuals on long-term therapy for clinical intervention to provide a better quality of life.
- Theme 2: The correlates of immune protection – Understanding the relationship of immune protection against viral diseases focusing mainly on RNA viruses using system biology approach to develop host directed therapies.
Ph.D. student Maike Sperk working in cell lab who along with others initiated the immune-metabolic research in the lab.
Illuminating the impact of inflamm-aging and metabolism on HIV-infected individuals
Inflamm-aging is something that all humans experience. It is aging characterized by a chronic, low-grade systemic inflammation. This process is a highly significant risk factor for both morbidity and mortality in older adults. In PLHIV, the inflamm-aging process is accelerated.
The group’s first theme of study, called AROGYA means well-being in Sanskrit and looks at the inflamm-aging process. The integrative omics project aims to unravel the physiological and molecular pathways that underline the premature aging of the immune system (immune-aging) and to potentially generate novel therapeutic approaches for age-related diseases with a focus on the PLHIV.
Applying high-throughput multi-omics technologies (e.g., transcriptomics, proteomics and metabolomics), along with in vitro and ex vivo experimental methods, the group’s research will help bridge the gap between genotype and phenotype to understand how it regulates inflamm-aging and age-related diseases in PLHIV.
The finding will provide possibilities to therapeutically target the inflamm-aging process through metabolic interference, thus allowing more individualized care.
“Despite existing scientific evidence suggesting that human aging in HIV-infected individuals is multifaceted, most of the laboratory-based studies to date have focused on specific pre-defined molecules or pathways, thereby ignoring the systemic, interconnected, immunological programs that are associated with the individual immune system,” says Neogi. “The application of advanced technologies with high-throughput proteomics and metabolomics and conventional immunological assays can, therefore, provide a frame of reference for what might be required in clinical intervention strategies to delay the premature or inflamm-aging- and the onset of age-related diseases in people living with HIV. Ultimately, our goal is to improve the quality of life for these patients.”
This research will result in new therapeutic targets and biomarkers for HIV-aging-related study and more detailed characterization of the patients’ HIV-specific immune system. Any new biomarkers will add significance to monitor treated HIV-1 patients, allowing more individualized care, independent on the clinical outcome of our study and it will open the area of precision medicine in managing PLHIV. Moreover the team’s recent study to understand the natural immune control mechanism in HIV-1 infected individuals may help in developing newer antiviral strategy.
Understanding the influences of immune protection against viral diseases
Dr. Neogi and his team at Karolinska have also focused on a second theme of study around influences of immune protection against viral diseases through interfering through the host-metabolic process. This work has involved examining immune-metabolism studies in HIV-1 infection to unravel the mystery of HIV-1 EC patients. These patients EC are a rare but heterogenous group of HIV-1-infected individuals who can suppress viral replication in the absence of antiretroviral therapy. While the mechanisms of how EC patients achieve undetectable viral loads remain unclear, the group’s work has begun to reveal insights into the mechanisms governing EC status. The first study, investigated host plasma metabolomics and targeted plasma proteomics in a Swedish HIV-1 cohort including EC and treatment-naïve viremic progressors (VP) as well as HIV-negative individuals (HC).
The Complete Picture
Metabolomics has greatly impacted Dr. Neogi’s work on both chronic and acute viral diseases by illuminating the mechanism providing a closer look at the phenotype. Viruses are dependent on the host cell machinery to promote anabolism (synthesis) needed for virion (virus particle) replication and assembly.
During the acute phase of infection, viral infection triggers metabolic reprogramming in host cells to facilitate optimal virus production. “Therefore, understanding the metabolic hijacking by the viruses during the acute phase of infection can provide important clue about the pathogenesis, and also provide opportunity to develop antivirals as well as vaccine strategies,” says Dr. Neogi. “In the case of chronic viral infections like HIV-1 where a cure or vaccine haven’t yet been achieved, metabolomics can provide important information of the systemic changes of the immune system due to persistent viral replication as well as long term treatment that may linked to the accelerated aging of the immune system.”
By identifying the nature of systemic metabolic changes, an intervention strategy can be developed to normalize the effects. Dr. Neogi is confident a similar model can be used with other infectious diseases.
Dr. Ujjwal Neogi
Associate Professor of Virology, Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden.
Adjunct Associate Professor, School of Medicine, University of Missouri, Columbia, USA.
Across the globe, there are 37.9 million persons living with HIV (PLWH). With access to antiretroviral therapy (ART), AIDS can be prevented, but the life expectancy for the PLWH is still shorter than in uninfected persons. They often suffer from age-related maladies which diminish their quality of life. My great passion is to understand the immune-metabolic abnormalities in PLWH under therapy which could be targeted by clinical or lifestyle intervention to provide healthy aging to PLWH. Therefore, my lab work towards unraveling the mechanism of immune aging in PLWH on long-term successful therapy to identify novel molecular mechanisms and biomarkers for potential future clinical intervention for healthy aging. My group also wants to understand the mechanisms of correlates of immune protection against viral infections that include HIV, Crimea Congo Hemorrhagic Fever (CCHF) viruses and dengue viruses (DENV) using multi-omics system biology approach amalgamating with in vitro and ex vivo experimental assays.
By training, I am a molecular virologist and obtained my doctoral (Ph.D.) degree in Medical Sciences from Karolinska Institutet (KI) in 2013. My expertise is in translation research pertaining to molecular virology, high-throughput sequencing and multi-omics technologies.