p53 IS AN IMPORTANT COMPONENT OF THE ANTIVIRAL RESPONSE

Di Gioacchino, Speranza L, Sanese G, Xhepa K. p53 is an integral component of the antiviral response.  International Journal of Infection. 2026;10(2):37-40.

M. Di Gioacchino^1*, L. Speranza¹, G. Sanese² and K. Xhepa²

¹ Department of Medicine and Ageing Sciences, University “G. D’Annunzio”, Chieti, Italy;
² Neurosciences Imaging and Clinical Sciences Department, University “G. D’Annunzio”, Chieti, Italy.

*Correspondence to:
Mario Di Gioacchino,
Department of Medicine and Ageing Sciences,
University “G. D’Annunzio”,
Chieti, Italy.
e-mail: dgioacchino@me.com

Received: 11 May, 2026 Accepted: 01 July, 2026

ISSN 3103-6678 [online] Copyright 2026 © by Biolife Publisher This publication and/or article is for individual use only and may not be further reproduced without written permission from the copyright holder. Unauthorized reproduction may result in financial and other penalties. Disclosure: all authors report no conflicts of interest relevant to this article.

ABSTRACT

The p53 protein, encoded by the TP53 gene, is an important tumor suppressor known as the “guardian of the genome” because it controls DNA integrity, arrests the cell cycle and promotes DNA repair or apoptosis in case of irreparable damage. In addition to its antitumor function, p53 plays a crucial role in the antiviral response, inhibiting viral replication, promoting cellular arrest and enhancing immune responses mediated by interferons and innate immunity. Mutations in the TP53 gene impair these protective functions and are present in approximately 50% of human tumors, including those associated with viral infections. During viral infections, p53 plays an important antiviral role by inducing apoptosis of infected cells through the activation of pro-apoptotic genes such as BAX, PUMA, and NOXA, and by blocking the cell cycle via p21, thus limiting viral replication. Furthermore, p53 enhances the immune response by collaborating with interferons and promoting the production of innate immune cytokines. Because it represents an obstacle to viral replication, many viruses have developed mechanisms to inactivate it, such as human papillomavirus (HPV) with the E6 protein, adenovirus with E1B-55K, and SV40 with the large T antigen. p53 is a key antiviral and tumor-suppressor protein that regulates cell-cycle arrest, DNA repair, apoptosis, and immune responses during viral infections. In chronic hepatitis caused by hepatitis B virus (HBV) and hepatitis C virus (HCV), viral proteins interfere with p53 activity to promote oxidative stress, impaired apoptosis, genomic instability, TP53 mutations such as R249S, and the development of hepatocellular carcinoma. Similarly, SARS-CoV-2 can induce p53 degradation to enhance viral replication and immune dysregulation, although p53 also contributes to antiviral defence by limiting viral spread, cooperating with interferons, and eliminating infected cells through apoptosis.

KEYWORDS: p53, gene, tumor suppressor, antiviral response, virus

INTRODUCTION

p53 is an important protein encoded by the TP53 gene and known as the “guardian of the genome” because it regulates the cell cycle, DNA repair, and apoptosis. p53 plays a role in maintaining stability by preventing mutations (1,2). The main function of p53 is to monitor DNA integrity, block the proliferation of damaged cells, and prevent tumor development (3).

In viral infections, p53 is a key component of the host’s antiviral response (4). p53 inhibits viral infections, participates in cell arrest, enhances the immune response exerted by interferon alpha and beta, and mediates innate immunity. In addition, p53 blocks the proliferation of damaged cells and prevents the onset of tumors (5). p53 levels are very low in the cell, but it is activated following cellular damage through a process of phosphorylation (6).

p53 is capable of halting cell replication in the G1 phase of the cell cycle by inducing DNA repair (7). Repair occurs by activating the expression of specific genes responsible for correcting genetic errors (8). Furthermore, if the cellular damage is severe and irreparable, p53 induces apoptosis, preventing the damaged cell from multiplying (9).  p53 is a ubiquitous protein expressed in all cells, and the TP53 gene is one of the most important tumor suppressor genes in the human body (10). Mutations in this gene lead to dysfunction of the p53 protein, which can cause tumors (11).  Mutations in this gene are very common and are present in approximately 50% of all human tumors, including those induced by viruses (12).

DISCUSSION

In viral infections, p53 induces apoptosis in infected cells (13). It can activate pro-apoptotic genes such as BAX, PUMA, and NOXA, inducing cell death before the virus completes its replication cycle (14). In a metabolically active cell, p53 can block the cell cycle via p21, thus inhibiting viral replication (15,16).  Interferons are viral inhibitors and interact with the p53 pathway, enhancing their biological activity and promoting the expression of various stimulated genes (17). Additionally, p53 can mediate the production of cytokines in the innate immune system (17,18). However, viruses counteract p53, which opposes viral replication, and have developed resistance mechanisms (19).

For example, the human papillomavirus (HPV) possesses an E6 protein capable of degrading p53 via the ubiquitin-proteasome system (20). In adenovirus, the E1B-55K protein binds and inactivates p53, while in SV40, the large T antigen sequesters p53, preventing it from exerting its biological effect (21). p53 plays an important role in virally transmitted hepatitis, where chronic infections promote the development of pathological effects such as tumors, inflammation, and immune dysregulation (22). The interaction between p53 and Hepatitis B virus (HBV) and Hepatitis C virus (HCV) is one of the most important mechanisms through which these chronic infections promote the development of hepatocellular carcinoma (23).

During infection, some viruses, such as HBV, can integrate their DNA into hepatocytes and alter p53 activity (24). In this context, the crucial viral protein is the HBV X protein (HBx), which binds to p53, inhibiting transcriptional activity and sequestering p53 in the cytoplasm, preventing it from reaching the nucleus (25). HBx also inhibits genes involved in apoptosis and DNA repair, an effect that allows infected cells to live longer and increases the number of mutations (14). Furthermore, the integration of viral DNA into the cellular genome alters the cellular genetic makeup and the action of p53 (26).

In infections with RNA viruses, such as HCV, there is no integration of the genome between the virus and the host cell, but chronic infection induces oxidative stress and inflammation (27). In this case, several proteins interact with p53, such as the “core” proteins NS3 and NS5A (28). By acting on p53, the “core” protein modulates transcriptional activity, reduces the efficiency of apoptosis, and alters the intracellular localization of p53 (29). The NS3 and NS5A proteins interfere with the signals that activate p53, alter the DNA damage response, and promote the survival of infected cells (28).

In HCV, there is continuous production of reactive oxygen species (ROS), activating repair mechanisms and oxidative DNA damage. p53 eliminates damaged cells, but viral interference reduces its effectiveness (30). Moreover, in HBV- and HCV-associated liver cancer, gene mutations of TP53 encoding p53 can occur, and the mutation at codon 249 (R249S) of the TP53 gene is the best known (31).

In SARS-CoV-2 infection, p53 can also be altered by viral proteins, causing its degradation (32).  This effect can promote viral replication and a dysregulated immune response. On the other hand, an excessive p53 response can cause apoptosis and tissue damage (33). Therefore, p53 can contribute to limiting viral shedding, eliminating infected cells, and preventing tissue damage. It blocks the proliferation of infected cells, acts in cooperation with interferons, and induces apoptosis (34).

CONCLUSIONS

p53 is a key antiviral protein that cooperates with interferons alpha and beta, blocks the proliferation of infected cells, and induces apoptosis. However, many viruses have developed specific strategies to neutralize p53 to defend themselves from its effects. In viral infections, the effect of p53 on the pathogenic virus is considered an important mechanism in viral disease and tumor development.

Conflict of interest

The authors declare that they have no conflict of interest.

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