Journal of Antivirals & Antiretrovirals
Open Access

Role of Host-Directed Therapies in Enhancing Antiviral Efficacy

Meklit Tesfaye^{* *}Correspondence: Meklit Tesfaye, Department of Molecular Virology, Colombo Institute of Biomedical Research, Sri Lanka, Email:

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The landscape of antiviral therapy is undergoing a transformative shift with growing interest in host-directed therapies (HDTs), which focus on modulating host cellular pathways rather than directly targeting viral components. This approach offers several compelling advantages, particularly in the era of emerging and re-emerging viral infections, where traditional antivirals often face challenges such as viral mutations and drug resistance. Unlike direct-acting antivirals (DAAs), which can be rendered ineffective by single point mutations in viral genomes, HDTs exploit relatively stable host mechanisms, potentially offering broader and more durable protection.

Host-directed therapies aim to enhance the innate and adaptive immune responses, modulate inflammation, improve tissue repair, and interrupt host pathways crucial for viral replication. A notable example includes the use of interferons, which stimulate a wide range of interferon-stimulated genes (ISGs) that can inhibit viral entry, replication, and egress. Although initially used in chronic hepatitis B and C, interferons are being revisited for newer applications such as SARS-CoV-2 and respiratory syncytial virus (RSV). Other immune modulators like toll-like receptor (TLR) agonists are also under investigation for their potential to trigger early antiviral defenses, reducing viral burden before significant pathology occurs.

Autophagy modulation is another promising avenue. Many viruses manipulate the host autophagy machinery to support their replication. Drugs that restore normal autophagic flux, such as rapamycin and its analogs, have shown potential in reducing viral load in diseases like dengue, influenza, and Zika. Similarly, cellular kinases like PI3K/AKT and MAPK pathways are exploited by several viruses and are thus attractive targets for therapeutic modulation. Inhibiting these pathways can simultaneously prevent viral replication and modulate immune responses, offering a dual benefit.

Metabolic reprogramming of host cells is another strategy being explored. Viruses often hijack cellular metabolism to meet their energy and biosynthetic needs. Drugs that target glycolysis, lipid metabolism, or mitochondrial function can deprive the virus of critical resources. For example, metformin, traditionally used in type 2 diabetes, has demonstrated antiviral properties through modulation of AMP-activated protein kinase (AMPK) and inhibition of mTOR signaling. These metabolic modulators may also improve disease outcomes by reducing inflammation and oxidative stress.

HDTs are particularly promising for viral diseases with limited or no effective antiviral treatments. In the case of Ebola virus, where conventional antivirals have limited efficacy, the modulation of coagulation and endothelial function through statins and angiotensin receptor blockers (ARBs) has shown survival benefits in small-scale studies. Similarly, in the COVID-19 pandemic, repurposing drugs such as dexamethasone, which controls hyperinflammation rather than directly inhibiting the virus, saved countless lives by mitigating the host cytokine storm that leads to severe disease.

However, the application of HDTs is not without challenges. One major concern is the specificity of host targets. Intervening in fundamental cellular processes can lead to unintended toxicity or compromise the immune system. Therefore, careful identification of targets that are critical for viral replication but dispensable for normal cell function is essential. Additionally, individual variability in immune response and genetics can influence the effectiveness of HDTs, making personalized medicine approaches particularly relevant.

Despite these challenges, the future of HDTs looks promising with advancements in systems biology, CRISPR screening, and single-cell transcriptomics, which are helping identify novel host factors and pathways involved in viral infections. Furthermore, combination therapies that pair HDTs with DAAs may offer synergistic benefits—reducing the chances of resistance, enhancing efficacy, and potentially shortening treatment durations. In diseases like HIV and HCV, such strategies may help target viral reservoirs that are otherwise inaccessible to conventional treatments.

In conclusion, host-directed therapies represent a paradigm shift in antiviral treatment strategies, focusing on the host rather than the virus. By targeting conserved host pathways and enhancing immune responses, HDTs provide a versatile and potentially resistance-proof strategy for managing viral infections. As our understanding of host-pathogen interactions deepens, and as drug development technologies evolve, the integration of HDTs into mainstream antiviral regimens is not only plausible but necessary for future pandemic preparedness and the effective management of chronic viral infections.