Stefania Varchetta ^1* Emanuela Marcenaro ^2,3*

• ¹ San Matteo Hospital Foundation (IRCCS), Pavia, Lombardy, Italy
• ² Department of Experimental Medicine, University of Genova, Genova, Italy
• ³ IRCCS Ospedale Policlinico San Martino, Genova, Italy, Genova, Italy

The primary objective of this Research Topic was to better understand the interplay between innate and adaptive immune responses in chronic viral infections, particularly how these infections alter immune function. Studies reviewed in this topic explored the immune dysfunction associated with chronic HCV infection and its broader implications for immune responses to other pathogens, including SARS-CoV-2.A key study by Maretti-Mira et al. (https://www.frontiersin.org/journals/virology/articles/10.3389/fviro.2023.1198361/full) demonstrated that chronic HCV infection disrupts the immune response to its antigens and shapes the broader immune landscape, impacting responses to other viral infections. Specifically, they found that chronic HCV infection induces immune modulation, leading to dysfunction in CD8+ T cells, which are crucial for viral clearance. Over time, these cells enter a state of exhaustion, impairing the immune system's ability to control the virus and other infections. These findings provide crucial insights into the broader impact of chronic viral infections on immune function.Similar patterns of immune dysregulation and T cell exhaustion were observed in both chronic HCV and acute SARS-CoV-2 infections, emphasizing the generalizability of immune dysfunction across diQerent viral infections. One of the central insights from this Research Topic is the phenomenon of immune exhaustion, which occurs in chronic viral infections. Both HCV and SARS-CoV-2 infections lead to T cell dysfunction, particularly in CD8+ T cells, which are essential for controlling viral replication. This dysfunction is marked by the upregulation of exhaustion markers like PD-1 and TIM-3, and a reduction in eQector memory T cell responses, hindering eQective immune clearance.The study by Maretti-Mira et al. illustrated how chronic HCV infection impairs HCV-specific CD8+ T cells and also alters immune responses to other co-infections, such as cytomegalovirus (CMV) and influenza. Indeed, these researchers found that CD8+ T cells specific to non-HCV viruses, like CMV and influenza, exhibited heightened cytotoxicity and a pro-inflammatory phenotype. This highlights how chronic infections broadly aQect the immune system, increasing susceptibility to secondary infections and complicating vaccine responses. These insights are particularly relevant for understanding SARS-CoV-2 infections, as patients with long COVID or concurrent viral infections exhibit similarly altered immune profiles.Recent studies have also highlighted the critical role of host restriction factors in limiting viral replication. In the case of SARS-CoV-2, host restriction factors-components of the innate immune system-act to inhibit the viral life cycle. In a study conducted in Nairobi, Kenya, Muhonja Otindo A et al. (https://www.frontiersin.org/journals/virology/articles/10.3389/fviro.2024.1479645/full) assessed SARS-CoV-2 seroprevalence and vaccine uptake in university students. The study found that 87.8% of participants had anti-SARS-CoV-2 IgG antibodies, suggesting widespread exposure to the virus, either through natural infection or vaccination. However, the study also revealed significant vaccine hesitancy (43.4%), with mistrust, health concerns, and lack of information cited as the main reasons. This highlights the importance of addressing vaccine hesitancy through community engagement and educational eQorts to improve vaccination uptake and ensure eQective public health interventions. The recent study of Crimean-Congo Hemorrhagic Fever Virus (CCHFV) in Senegal (https://www.frontiersin.org/journals/virology/articles/10.3389/fviro.2024.1498672/abstract) provides additional insights into viral infection and immune response. The study observed a high IL-6 titer, low IL-10 titer, and delayed IgG response in a fatal CCHFV case. These biomarkers may serve as indicators of disease severity, allowing for early intervention and tailored treatment strategies for severe infections. The manipulation of host DNA repair mechanisms by viruses also emerged as a significant theme in this research topic. Both HCV and SARS-CoV-2 exploit host cell machinery, including DNA repair pathways, to avoid immune detection and sustain viral replication. A review by Saladino et al. (https://www.frontiersin.org/journals/virology/articles/10.3389/fviro.2024.1410258/full) explored how viruses alter cellular repair pathways, promoting viral survival and contributing to immune dysfunction. These mechanisms underscore the complexity of viral persistence and oQer potential targets for antiviral therapies. Additionally, a study conducted in Uganda among people living with HIV (PLWH) revealed a 93% SARS-CoV-2 seroprevalence among unvaccinated individuals, despite a relatively low proportion of participants having a laboratory-confirmed infection. This high seroprevalence could be attributed to widespread exposure to the Omicron variant following the lifting of restrictions. The findings reinforce the idea that while humoral immunity (i.e., antibodymediated immunity) can be robust in certain populations, the asymptomatic or mild nature of many infections could lead to underreporting of true infection rates. These results have important implications for understanding immune responses in PLWH, where previous exposure to SARS-CoV-2 may enhance immune readiness, even without formal diagnosis or vaccination (https://www.frontiersin.org/journals/virology/articles/10.3389/fviro.2024.1429785/full). The study underscores the potential for high antibody concentrations despite a low rate of confirmed infections, suggesting a robust immune response that could inform future vaccine strategies. While this Research Topic has significantly advanced our understanding of immune dysfunction in chronic viral infections, several key questions remain. Future research should further investigate the mechanisms of T cell exhaustion, particularly the role of epigenetic changes, cellular metabolism, and microenvironmental factors in driving T cell dysfunction. Understanding these processes could lead to novel therapeutic strategies aimed at rejuvenating exhausted T cells in chronic and emerging viral infections.Another promising direction is the exploration of immune checkpoint manipulation in chronic infections. Both HCV and SARS-CoV-2 exploit immune checkpoints like PD-1 and TIM-3 to evade immune surveillance. Developing therapies that target these pathways could enhance viral clearance and promote immune recovery, particularly for patients suQering from long COVID or other post-viral syndromes.Additionally, future studies should examine how chronic infections impact vaccine eQicacy. Chronic infections like HCV can alter T cell responses to other pathogens, which may aQect how the immune system responds to vaccines. Understanding these dynamics is crucial for developing tailored vaccine strategies. The insights from this Research Topic emphasize the complexity of immune responses in chronic viral infections. Both HCV and SARS-CoV-2 illustrate the ways in which viruses modulate immune function, especially through T cell exhaustion and immune dysfunction. These findings are critical for developing novel therapeutic strategies that not only clear the virus but also restore immune function and prevent long-term complications.Future research into host restriction factors, immune modulation, and viral manipulation of host DNA repair mechanisms holds promise for advancing antiviral therapies. As we continue to unravel the mechanisms behind immune dysregulation, we can develop integrated approaches to manage chronic infections more eQectively, improving public health outcomes and addressing the long-term consequences of viral infections.