Virology & Mycology
Open Access

Immunomodulation Strategies in Persistent Viral and Fungal Infections

Radhika Mehra^{* *}Correspondence: Radhika Mehra, Department of Immunology and Infectious Diseases, National Institute of Medical Sciences, New Delhi, India, Email:

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Description

Persistent viral and fungal infections present some of the most challenging clinical scenarios due to their ability to evade or suppress the host immune response, leading to chronic disease states. Unlike acute infections that resolve with a robust immune reaction or effective pharmacological intervention, persistent infections often manipulate immune mechanisms to survive within the host for extended periods. This is particularly evident in infections caused by viruses like HIV, hepatitis B virus (HBV), and human papillomavirus (HPV), and by fungal pathogens such as Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus. These organisms develop mechanisms to establish long-term residence in immune-privileged sites or subvert host immunity through antigenic variation, immune cell exhaustion, and modulation of cytokine profiles. In response, the medical and scientific community is increasingly exploring immunomodulation strategies—therapeutic approaches that enhance or restore immune functions—as a promising adjunct to traditional antiviral or antifungal drugs.

In the context of viral infections, immunomodulation strategies primarily focus on reinvigorating T-cell responses and reversing immune exhaustion. Chronic infections like HIV and HBV are known to induce high levels of inhibitory receptors such as PD-1 and CTLA-4 on T cells, which significantly dampen the immune response. Immunotherapies targeting these checkpoints, such as PD-1/PD-L1 inhibitors, are currently being evaluated for their potential to reactivate antiviral immune responses. Additionally, therapeutic vaccines are being developed to enhance specific immune memory against viral antigens. For instance, in chronic hepatitis B, therapeutic vaccination aims to prime cytotoxic T lymphocytes to eliminate infected hepatocytes. Interleukin-based therapies, particularly those involving IL-2, IL-7, and IL-15, are also being tested to support T-cell survival and proliferation in chronic viral infections.

Similarly, fungal pathogens exploit immune evasion tactics such as biofilm formation, phenotypic switching, and secretion of immunosuppressive molecules. Immunomodulation in fungal infections aims to boost innate immunity, especially the activity of phagocytic cells like macrophages and neutrophils. One such strategy involves the use of granulocyte-macrophage colony-stimulating factor (GM-CSF) to enhance the recruitment and activation of innate immune cells. This has shown promise in invasive candidiasis and pulmonary aspergillosis, particularly in immunocompromised patients. Another approach is adoptive immunotherapy, where pathogen-specific T cells or Natural Killer (NK) cells are expanded ex vivo and infused into the patient to provide a targeted immune response. Monoclonal antibodies targeting fungal cell wall components, such as β-glucans or mannoproteins, are also being developed to aid opsonization and clearance by host immunity.

The synergy between antifungal or antiviral drugs and immunomodulators is crucial for clearing persistent infections. For example, antifungal drugs like echinocandins and azoles often require intact immune responses to achieve complete eradication of the infection. Immunocompromised patients with neutropenia or hematologic malignancies, despite receiving appropriate antifungal treatment, often experience relapse or treatment failure. In such cases, adjunctive therapies aimed at immune reconstitution like hematopoietic growth factors or cytokine therapy can significantly improve outcomes. Similarly, in HIV-associated cryptococcal meningitis, Immune Reconstitution Inflammatory Syndrome (IRIS) remains a significant concern, necessitating careful balance between restoring immunity and avoiding hyperinflammation.

Moreover, emerging biotechnological advances are contributing to next-generation immunomodulation strategies. CRISPR-based gene editing holds potential for engineering immune cells to resist viral infection or enhance fungal recognition. Nanoparticle-based delivery systems are being investigated to deliver immunomodulatory agents directly to infection sites, minimizing systemic toxicity. The role of the host microbiome is also gaining attention, with studies suggesting that microbial-derived metabolites can influence immune responses to both viral and fungal pathogens. Probiotics and dietary interventions that modulate gut flora may thus become adjunct strategies in managing persistent infections.

In the Indian context, where fungal infections like mucormycosis and chronic candidiasis are increasingly reported among diabetic and immunosuppressed populations, and viral diseases such as hepatitis and HIV continue to impose a heavy burden, tailored immunomodulatory interventions are essential. Limited access to high-end biological therapies underscores the need for cost-effective, scalable approaches such as cytokine therapy, repurposed immunomodulators, and immune-based diagnostics that can be integrated into routine clinical care.

In conclusion, immunomodulation represents a promising frontier in the fight against persistent viral and fungal infections. By complementing traditional antimicrobial therapies with immune-enhancing interventions, clinicians can potentially achieve more durable and complete pathogen clearance, reduce recurrence, and improve patient outcomes. Continued investment in translational research, particularly in resource-limited settings like India, will be vital to harness the full potential of these strategies. Collaborative efforts between immunologists, infectious disease experts, and healthcare policymakers are required to integrate immunomodulation into comprehensive infectious disease management frameworks.