Viral Oncogenesis: Synergistic Role of Genome Integration and Persistence

Abstract

Persistence is a strategy used by many viruses to evade eradication by the immune system, ensuring their permanence and transmission within the host and optimizing viral fitness. During persistence, viruses can trigger various phenomena, including target organ damage, mainly due to an inflammatory state induced by infection, as well as cell proliferation and/or immortalization. In addition to immune evasion and chronic inflammation, factors contributing to viral persistence include low-level viral replication, the accumulation of viral mutants, and, most importantly, maintenance of the viral genome and reliance on viral oncoprotein production. This review focuses on the process of genome integration, which may occur at different stages of infection (e.g., HBV), during the chronic phase of infection (e.g., HPV, EBV), or as an essential part of the viral life cycle, as seen in retroviruses (HIV, HTLV-1). It also explores the close relationship between integration, persistence, and oncogenesis. Several models have been proposed to describe the genome integration process, including non-homologous recombination, looping, and microhomology models. Integration can occur either randomly or at specific genomic sites, often leading to genome destabilization. In some cases, integration results in the loss of genomic regions or impairs the regulation of oncogene and/or oncosuppressor expression, contributing to tumor development.

Keywords: Epstein–Barr virus; episome; genome integration; hepatitis B virus; latency; oncogenic viruses; papillomavirus; persistence; retrovirus.

Figure 1

Proposed models for HPV integration process into the host genome. (A) The Looping Model suggests that the viral DNA forms loop structures, facilitating its integration into the host genome through breakage and subsequent repair mechanisms at the integration site. (B) The Microhomology Model proposes that integration occurs via regions of microhomology (MH) between the viral and host DNA, enabling alignment and recombination during repair processes.

Figure 2

Schematic representation of the Epstein–Barr Virus (EBV) genome and associated latency programs. The EBV genome is illustrated, highlighting key regions and genes involved in viral latency. Latency states are characterized by distinct expression profiles, critical for the virus’s ability to evade immune responses and establish persistent infection. Abbreviations: EBERs, EBV-encoded small RNAs; Cp, C promoter; Wp, W promoter; EBNA-LP, EBV Nuclear Antigen-Leader Protein; EBNA2, EBV Nuclear Antigen 2; BHRF1, BamHI fragment H rightward open reading frame 1; Qp, Q promoter; EBNA3, EBV Nuclear Antigen 3; EBNA1, EBV Nuclear Antigen 1; BARTs, BamHI-A Rightwards Transcripts; LMP1, Latent Membrane Protein 1; LMP1p, LMP1 promoter; LMP2A, B, Latent Membrane Protein 2A, B; LMP2p, LMP2 promoter.

Figure 3

HIV integration process. After the reverse transcription of HIV RNA, the integrase enzyme performs 3′-processing, leaving the CA dinucleotide extending at both 5′ ends of the HIV genome. Following nuclear translocation, HIV strand transfer occurs, where integrase mediates the cleavage and insertion of viral DNA into the host genome. The CA dinucleotide at the 5′ ends is excised, and the resulting gaps are repaired by cellular genome repair mechanisms, completing the HIV integration process.