Periodic Reporting for period 1 - EPIVINF (Epigenetic regulation of host factors in viral infections (EPIVINF))
Reporting period: 2022-09-01 to 2024-02-29
Viral infections, including SARS-CoV-2 and HIV, can cause significant mortality and morbidities. For one, HIV infection causes continuous erosion of immune competence against the virus itself and co-pathogens that can cause further disease. Importantly, even in the presence of effective suppressive antiretroviral treatment (ART), up to 50% of chronically infected individuals develop some form of mild to severe neurocognitive decline over the years. With the population of HIV-infected individuals aging continuously (thanks to increasing ART availability), such neurological decay is expected to become even more pronounced. Yet, the understanding of the mechanisms leading to these neurological defects, potential biomarkers for their early diagnosis, and treatment options remain very limited.
In the case of SARS-CoV-2 infection, sometimes severe neurological disease has been noted from the earliest days of the Covid-19 pandemic. As the pandemic progressed, it became also evident that approximately 10-15% of the infected individuals may continue to experience Covid-19 related disease after the initial infection has resolved. This situation has been recognized by the WHO as the separate disease entity of “Long Covid” or “Post Covid-19 condition (PCC)”, which may affect in Europe alone 15+ million individuals. In a significant proportion of these individuals, disease manifestation includes neurological symptoms, which we here refer to as “Neuro Long Covid”. This disease spectrum includes a wide range of symptoms, which often are considered subjective perceptions, rather than representing objective measurements of some clinical parameter or biomarker. There is therefore common skepticism in the general public, among medical professionals, health insurances and among public health authorities as to the existence and nature of (Neuro) Long Covid. This has led to major frustration and medical abandonment of affected people and slowed progress in understanding the mechanisms, biomarkers and prognosis of this disease.
Disease persistence or progression in chronically persistent infections, such as HIV, have been linked to effects of ongoing viral replication and inflammation. The reasons for prolonged disease manifestation after supposedly only transient infections, such as SARS-CoV-2 infection, remain less well understood. The EPIVINF project is based on the hypothesis that immunological and epigenetic mechanisms triggered during the acute infection stages are determining the longer-term outcomes of these infections. Epigenetic regulation of host genes´ activity can be mediated by different mechanisms, which, as a general principle, lead to reduced amounts of the specific proteins being produced. Some of these mechanisms are considered to be stable over time, so that events during an acute infection could well persist long after the pathogen has been cleared from the body. Thus, our project centers especially on epigenetic dysregulation of host factors that are central for pathogen control and resolution of disease in the long term. We are thereby especially interested in mechanisms that are drivers of neurological long-term disease and how their identification could help develop novel therapeutic tools as the prevention and treatment of the neurological impact of these infections remains an enormous unmet medical need.
In the case of SARS-CoV-2 infection, sometimes severe neurological disease has been noted from the earliest days of the Covid-19 pandemic. As the pandemic progressed, it became also evident that approximately 10-15% of the infected individuals may continue to experience Covid-19 related disease after the initial infection has resolved. This situation has been recognized by the WHO as the separate disease entity of “Long Covid” or “Post Covid-19 condition (PCC)”, which may affect in Europe alone 15+ million individuals. In a significant proportion of these individuals, disease manifestation includes neurological symptoms, which we here refer to as “Neuro Long Covid”. This disease spectrum includes a wide range of symptoms, which often are considered subjective perceptions, rather than representing objective measurements of some clinical parameter or biomarker. There is therefore common skepticism in the general public, among medical professionals, health insurances and among public health authorities as to the existence and nature of (Neuro) Long Covid. This has led to major frustration and medical abandonment of affected people and slowed progress in understanding the mechanisms, biomarkers and prognosis of this disease.
Disease persistence or progression in chronically persistent infections, such as HIV, have been linked to effects of ongoing viral replication and inflammation. The reasons for prolonged disease manifestation after supposedly only transient infections, such as SARS-CoV-2 infection, remain less well understood. The EPIVINF project is based on the hypothesis that immunological and epigenetic mechanisms triggered during the acute infection stages are determining the longer-term outcomes of these infections. Epigenetic regulation of host genes´ activity can be mediated by different mechanisms, which, as a general principle, lead to reduced amounts of the specific proteins being produced. Some of these mechanisms are considered to be stable over time, so that events during an acute infection could well persist long after the pathogen has been cleared from the body. Thus, our project centers especially on epigenetic dysregulation of host factors that are central for pathogen control and resolution of disease in the long term. We are thereby especially interested in mechanisms that are drivers of neurological long-term disease and how their identification could help develop novel therapeutic tools as the prevention and treatment of the neurological impact of these infections remains an enormous unmet medical need.
To study epigenetic signatures and their relationship with persistent neurological disease, we have assembled an international team that has a long track record in HIV related clinical care and translational research and has been at the forefront of the medical response to the Covid-19 pandemic in some of the most hart hit countries in Europe. All clinical centers involved have established specific cohorts and clinical services for patients with Long Covid, in many cases individuals with clinical symptoms consistent with Neuro Long Covid. Equally, we include in our team two of the most important HIV-related clinical centers in Europe, with physicians and neurologists attending to individuals with HIV related neurocognitive disorder (HAND). Across more than a dozen different, mostly established cohorts and clinical trials, we have identified individuals with Neuro-HIV, Neuro Long Covid and individuals with either one or both of these infections who undergo Covid-19 vaccination or experimental therapeutic HIV immunization. Samples from these cohorts have by now entered the experimental work flow, and have predominantly been used for whole genome methylome and transcriptomics analyses, either on bulk cell subsets or on single cells.
Few data have been generated and analyzed within this first reporting period of EPIVINF. Based on emerging data, an outstanding feature will be the data that we have started to analyze on the methylation and gene transcription profiles in cells harvested from the peripheral blood or the spinal fluid from individuals with Neuro Long Covid (see Figure 1)