—Modulation of Host Immune Responses by Antiviral Agents

Antiviral agents not only directly inhibit viral replication but also play a crucial role in modulating host immune responses. This modulation is an essential aspect of antiviral therapy because viruses have evolved various strategies to evade or suppress the immune system. Antiviral agents can enhance the host’s immune defenses, prevent viral immune evasion, and improve the overall effectiveness of the immune response against viral infections.

Key Mechanisms of Immune Modulation by Antiviral Agents

1. Activation of Innate Immune Responses
   • Many antiviral agents stimulate or restore components of the innate immune system, particularly interferon (IFN) pathways, which are critical in early viral defense. Innate immunity provides the first line of defense against viral infections and sets the stage for the adaptive immune response.
   • Interferon Induction
     • Some antivirals, especially those mimicking viral components (e.g., synthetic nucleic acids or pattern recognition receptor agonists), can activate pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) or RIG-I-like receptors (RLRs). This activation leads to the production of type I interferons (IFN-α, IFN-β) and type III interferons (IFN-λ), which establish an antiviral state in host cells by inducing the expression of interferon-stimulated genes (ISGs).
     • Example: Imiquimod, an immune response modifier, stimulates TLR7, leading to the production of interferons and cytokines, enhancing the antiviral response against HPV (human papillomavirus).
2. Enhancement of Adaptive Immune Responses
   • Adaptive immunity, including T cells and B cells, is crucial for clearing viral infections and providing long-term immunity. Some antiviral agents modulate the adaptive immune system, particularly by enhancing T-cell responses or stimulating the production of neutralizing antibodies.
   • Boosting T-cell Activity
     • Certain antivirals can enhance cytotoxic T-lymphocyte (CTL) responses, which are vital for recognizing and killing virus-infected cells.
     • Example: Therapeutic vaccines in combination with antiviral drugs, such as in the treatment of HIV, aim to stimulate specific T-cell responses against viral antigens.
   • Antibody Responses
     • Some antiviral therapies are designed to enhance the production of neutralizing antibodies that target viral antigens, aiding in the neutralization of free virus particles.
     • Monoclonal antibodies: Passive immunotherapy using monoclonal antibodies can directly neutralize viruses by binding to viral surface proteins, preventing their attachment and entry into host cells. This has been applied in therapies for RSV (Respiratory Syncytial Virus), COVID-19, and Ebola.
3. Blocking Viral Immune Evasion Mechanisms
   • Many viruses have evolved strategies to evade detection by the host immune system, such as inhibiting interferon responses, downregulating major histocompatibility complex (MHC) molecules, or suppressing apoptosis. Antiviral agents can counteract these viral immune evasion tactics.
   • Restoring Interferon Responses
     • Some viruses, like hepatitis C virus (HCV), suppress the host’s interferon response to evade immune detection. Antiviral agents can reverse this suppression, allowing the immune system to mount a proper antiviral response.
     • Example: Direct-acting antivirals (DAAs) against HCV not only inhibit viral replication but also restore interferon signaling pathways, enhancing the innate immune response.
   • Inhibiting Viral Suppression of MHC Molecules
     • Viruses like HIV and CMV (Cytomegalovirus) can downregulate MHC molecules on infected cells, making them invisible to T cells. Antivirals that inhibit this process can help restore antigen presentation and recognition by T cells.
4. Modulation of Immune Checkpoints
   • Some antiviral therapies target immune checkpoint pathways, which regulate immune activation and prevent overactivation that can lead to immunopathology. Checkpoint inhibitors are used to reinvigorate exhausted T cells, especially in chronic viral infections such as HIV and Hepatitis B.
   • PD-1/PD-L1 Pathway
     • Viruses can induce the expression of immune checkpoint molecules such as PD-1 on T cells, leading to T-cell exhaustion and impaired immune responses. Inhibitors of the PD-1/PD-L1 axis (used in cancer immunotherapy) are being explored to boost T-cell function in chronic viral infections.
     • Example: In chronic HBV infections, checkpoint inhibitors could enhance T-cell activity and help in controlling the infection more effectively when combined with antiviral drugs.
5. Immunomodulatory Antivirals
   • Some antiviral agents have inherent immunomodulatory properties that can modify the host immune response, beyond their direct antiviral effects.
   • Ribavirin
     • Ribavirin, used to treat HCV and RSV, not only inhibits viral RNA synthesis but also modulates immune responses by altering cytokine production, shifting the immune profile towards a Th1 response, which is more effective against viral infections.
   • Immunomodulatory Drugs in COVID-19
     • Drugs like dexamethasone have been used in COVID-19 to reduce the hyperactive immune response (cytokine storm) associated with severe disease. Though not directly antiviral, these immunomodulators help manage immune-mediated damage while antiviral drugs target the virus.
6. Vaccine-Adjuvant-Like Effects
   • Some antiviral agents can act as vaccine adjuvants, enhancing the immune response to viral infections or boosting the effectiveness of therapeutic vaccines.
   • Example: CpG oligonucleotides, synthetic DNA sequences mimicking bacterial DNA, act as TLR9 agonists and have been used as adjuvants to boost immune responses in vaccines for hepatitis B and HPV.
7. Antiviral Agents that Modulate Cytokine Networks
   • Cytokines are signaling molecules that play a critical role in orchestrating the immune response to viral infections. Some antiviral agents target cytokine networks to modulate immune responses, either by enhancing protective cytokines or by suppressing harmful ones (e.g., cytokine storms in severe viral infections).
   • Interleukin (IL)-2 and IL-7
     • These cytokines are involved in the activation and proliferation of T cells. Some antiviral therapies include administration of recombinant IL-2 or IL-7 to enhance T-cell recovery and function in immunosuppressed patients, such as those with HIV.
   • Targeting IL-6 in COVID-19
     • Elevated levels of IL-6 are associated with severe COVID-19 and cytokine storms. Tocilizumab, an IL-6 receptor blocker, has been used in severe cases to reduce inflammation and immune-mediated damage.
8. Host-Targeted Antivirals (HTAs)
   • Instead of directly targeting the virus, some antiviral agents are designed to modulate host cell pathways critical for viral replication or immune evasion. By targeting host factors, these therapies aim to both inhibit viral replication and enhance the host immune response.
   • Example: Plitidepsin, a host-targeted antiviral in development for SARS-CoV-2, inhibits the eukaryotic translation elongation factor eEF1A, reducing viral replication while modulating immune responses.

Examples of Antiviral Agents Modulating Immune Responses

1. Interferon-Based Therapies
   • Interferon-α and interferon-β are used to treat chronic viral infections like hepatitis B and hepatitis C. These therapies work by stimulating the production of antiviral proteins and enhancing the immune system’s ability to recognize and eliminate infected cells.
2. Checkpoint Inhibitors in Viral Infections
   • Immune checkpoint inhibitors, such as anti-PD-1 antibodies, have been explored in chronic infections like HIV and hepatitis B, where they aim to reverse T-cell exhaustion and restore effective immune responses against the virus.
3. Monoclonal Antibodies (mAbs)
   • mAbs against viral antigens or immune components, such as palivizumab for RSV or tocilizumab for IL-6 in COVID-19, can neutralize viral particles or modulate the immune response to prevent excessive inflammation.
4. Host-Targeting Therapies
   • Agents like cyclosporine and sirolimus modulate immune responses by targeting host pathways involved in immune regulation, while also showing antiviral properties against viruses like HIV and hepatitis C.

Modulation of host immune responses by antiviral agents is a critical aspect of effective antiviral therapy. By enhancing innate and adaptive immunity, blocking viral immune evasion, targeting cytokine networks, and employing host-targeted strategies, these agents not only inhibit viral replication but also help the immune system clear the infection more efficiently. This dual approach of direct viral inhibition and immune modulation is increasingly important in the treatment of chronic viral infections and emerging viral diseases like COVID-19.