🦠Virology Unit 19 – Viruses and Cancer – Oncogenic Viruses

Viral Basics and Cancer Connection

• Viruses are obligate intracellular parasites that rely on host cells for replication and survival
• Certain viruses, known as oncogenic viruses, have the ability to cause cancer in humans and animals
• Oncogenic viruses can induce cellular transformation by altering host cell signaling pathways and disrupting normal cell cycle regulation
• These viruses often establish persistent infections, allowing for prolonged exposure to viral oncoproteins
  • Persistent infections can lead to chronic inflammation and oxidative stress, contributing to carcinogenesis
• Viral oncogenesis is a multistep process involving the accumulation of genetic and epigenetic alterations in host cells
• Oncogenic viruses are responsible for a significant portion of human cancers worldwide (cervical cancer, liver cancer, Kaposi's sarcoma)
• The study of oncogenic viruses has provided valuable insights into the molecular mechanisms of cancer development and progression

Types of Oncogenic Viruses

• DNA viruses: Viruses that have DNA as their genetic material and can directly integrate into the host genome or maintain their genome as episomes
  • Examples include human papillomavirus (HPV), Epstein-Barr virus (EBV), hepatitis B virus (HBV), and Kaposi's sarcoma-associated herpesvirus (KSHV)
• RNA viruses: Viruses that have RNA as their genetic material and typically do not integrate into the host genome
  • Examples include hepatitis C virus (HCV) and human T-cell lymphotropic virus type 1 (HTLV-1)
• Retroviruses: RNA viruses that use reverse transcriptase to convert their RNA genome into DNA, which can then integrate into the host genome
  • Examples include human immunodeficiency virus (HIV) and various animal retroviruses (Rous sarcoma virus, mouse mammary tumor virus)
• Different oncogenic viruses are associated with specific types of cancers
  • HPV: Cervical, anal, and oropharyngeal cancers
  • EBV: Burkitt's lymphoma, nasopharyngeal carcinoma, and Hodgkin's lymphoma
  • HBV and HCV: Hepatocellular carcinoma
  • KSHV: Kaposi's sarcoma and primary effusion lymphoma
• Some oncogenic viruses exhibit tissue tropism, preferentially infecting and transforming specific cell types

Mechanisms of Viral Oncogenesis

• Viral oncoproteins: Oncogenic viruses express specific proteins that can interfere with host cell signaling pathways and promote cellular transformation
  • These oncoproteins often mimic or inhibit the function of cellular proteins involved in cell cycle regulation, apoptosis, and DNA repair
• Viral integration: Some DNA viruses (HPV, HBV) can integrate their genetic material into the host genome, potentially disrupting tumor suppressor genes or activating proto-oncogenes
• Epigenetic alterations: Oncogenic viruses can induce epigenetic changes in host cells, such as DNA methylation and histone modifications, leading to altered gene expression and genomic instability
• Chronic inflammation: Persistent viral infections can cause chronic inflammation, which creates a microenvironment conducive to cancer development
  • Inflammation leads to the production of reactive oxygen species (ROS) and cytokines that promote cell proliferation and survival
• Immune evasion: Oncogenic viruses have evolved mechanisms to evade the host immune response, allowing for prolonged viral persistence and increasing the risk of cellular transformation
• Cooperation with other carcinogens: Oncogenic viruses can act synergistically with other carcinogenic factors, such as chemical carcinogens or UV radiation, to promote cancer development
• Modulation of cell metabolism: Some oncogenic viruses can alter host cell metabolism to support viral replication and cellular transformation

Key Viral Oncoproteins

• E6 and E7 (HPV): Inactivate tumor suppressor proteins p53 and pRb, respectively, leading to uncontrolled cell proliferation and genomic instability
• LMP1 and EBNA proteins (EBV): Mimic cellular signaling pathways, such as NF-κB and PI3K/Akt, to promote cell survival and proliferation
• HBx (HBV): Interacts with various cellular proteins to modulate gene expression, cell cycle regulation, and apoptosis
• Tax and HBZ (HTLV-1): Activate transcription factors (CREB, NF-κB) and interfere with tumor suppressor functions, leading to T-cell transformation
• NS5A and core proteins (HCV): Modulate host cell signaling pathways and contribute to the development of hepatocellular carcinoma
• v-Src (Rous sarcoma virus): A viral homolog of the cellular Src kinase that constitutively activates signaling pathways involved in cell growth and survival
• These viral oncoproteins often target multiple cellular pathways and can cooperate with each other to enhance their transforming potential

Cellular Pathways Targeted by Oncogenic Viruses

• p53 pathway: Many viral oncoproteins (HPV E6, adenovirus E1B) target and inactivate the tumor suppressor protein p53, which normally functions to induce cell cycle arrest or apoptosis in response to DNA damage or cellular stress
• Retinoblastoma (Rb) pathway: Viral oncoproteins (HPV E7, adenovirus E1A) bind and inactivate the Rb protein, releasing the E2F transcription factor and promoting cell cycle progression
• NF-κB pathway: Several oncogenic viruses (EBV, KSHV, HTLV-1) activate the NF-κB transcription factor, which regulates genes involved in inflammation, cell survival, and proliferation
• PI3K/Akt pathway: Viral oncoproteins (EBV LMP1, HPV E6) can activate the PI3K/Akt signaling pathway, promoting cell survival and growth
• MAPK pathways: Oncogenic viruses can modulate mitogen-activated protein kinase (MAPK) pathways, such as ERK and JNK, to influence cell proliferation and survival
• Wnt/β-catenin pathway: Some viral oncoproteins (HBV HBx, HPV E6) can activate the Wnt/β-catenin signaling pathway, which plays a role in cell fate determination and proliferation
• TGF-β pathway: Oncogenic viruses can interfere with the transforming growth factor-beta (TGF-β) signaling pathway, which normally functions to inhibit cell growth and promote differentiation
• By targeting these critical cellular pathways, oncogenic viruses can promote the hallmarks of cancer, such as sustained proliferative signaling, evasion of growth suppressors, and resistance to cell death

Host Immune Response to Oncogenic Viruses

• Innate immune response: The first line of defense against viral infections, including the production of type I interferons (IFN-α/β) and activation of natural killer (NK) cells
  • Oncogenic viruses have evolved mechanisms to counteract the innate immune response, such as inhibiting interferon production or signaling
• Adaptive immune response: The development of virus-specific antibodies and T-cell responses that help to control viral infection and prevent the spread of infected cells
  • CD8+ cytotoxic T lymphocytes (CTLs) play a crucial role in recognizing and eliminating virus-infected cells
  • However, oncogenic viruses can evade CTL responses through various mechanisms, such as downregulating MHC class I expression or producing immunosuppressive cytokines
• Humoral immunity: The production of neutralizing antibodies that can bind to viral particles and prevent their entry into host cells
  • While antibodies are important for preventing initial infection, they may be less effective against established tumors or virus-infected cells
• Immunosuppression: Some oncogenic viruses (HIV, EBV) can cause immunosuppression, impairing the host's ability to mount an effective immune response against the virus and virus-induced tumors
• Chronic inflammation: Persistent viral infections can lead to chronic inflammation, which can create an immunosuppressive microenvironment that favors tumor growth and progression
• Immune evasion strategies: Oncogenic viruses have developed various mechanisms to evade the host immune response, such as encoding decoy receptors for immune signaling molecules or producing viral homologs of cellular cytokines (virokines)
• Immunotherapy: Understanding the immune response to oncogenic viruses has led to the development of immunotherapeutic approaches, such as therapeutic vaccines and adoptive T-cell therapy, to boost the host's anti-tumor immunity

Diagnostic Methods and Biomarkers

• Serological tests: Detection of virus-specific antibodies in patient serum, indicating current or past infection
  • Examples include enzyme-linked immunosorbent assay (ELISA) and Western blot
• Molecular tests: Detection of viral nucleic acids (DNA or RNA) in clinical samples using polymerase chain reaction (PCR) or other amplification methods
  • Quantitative PCR can be used to monitor viral load and disease progression
• Immunohistochemistry: Detection of viral antigens in tissue samples using specific antibodies, allowing for the visualization of virus-infected cells
• In situ hybridization: Detection of viral nucleic acids in tissue sections using labeled complementary probes, providing information on the localization of viral genomes
• Viral integration analysis: Assessment of viral integration sites in the host genome using techniques such as Southern blot, inverse PCR, or next-generation sequencing
• Biomarkers: Identification of cellular or viral markers that can aid in the diagnosis, prognosis, or monitoring of virus-associated cancers
  • Examples include the expression of viral oncoproteins (HPV E6/E7, EBV LMP1), cellular tumor suppressors (p16), or immune markers (PD-L1)
• Screening programs: Implementation of population-based screening for oncogenic virus infections or virus-associated precancerous lesions
  • Examples include HPV testing for cervical cancer screening and HBV/HCV testing for liver cancer risk assessment
• Liquid biopsy: Analysis of circulating tumor cells, cell-free DNA, or exosomes in blood samples to detect viral biomarkers or monitor treatment response
• Integration of multiple diagnostic methods can improve the accuracy and specificity of detecting oncogenic virus infections and virus-associated cancers

Prevention and Treatment Strategies

• Vaccination: Development of prophylactic vaccines to prevent initial infection with oncogenic viruses
  • Successful examples include the HPV vaccine (Gardasil, Cervarix) and the HBV vaccine
  • Therapeutic vaccines targeting viral oncoproteins or tumor-associated antigens are also being explored
• Antiviral therapy: Use of antiviral drugs to inhibit viral replication and reduce the risk of virus-associated cancers
  • Examples include nucleoside analogs (tenofovir, entecavir) for HBV treatment and direct-acting antivirals (sofosbuvir, ledipasvir) for HCV treatment
• Screening and early detection: Implementation of screening programs to identify precancerous lesions or early-stage cancers, allowing for timely intervention and improved outcomes
  • Examples include Pap smear and HPV testing for cervical cancer screening and alpha-fetoprotein (AFP) testing for liver cancer surveillance in high-risk populations
• Targeted therapies: Development of drugs that specifically target viral oncoproteins or the cellular pathways they dysregulate
  • Examples include small molecule inhibitors of viral enzymes (HIV protease inhibitors) or cellular kinases (BCR-ABL inhibitors for EBV-associated lymphomas)
• Immunotherapy: Harnessing the host immune system to recognize and eliminate virus-infected or transformed cells
  • Approaches include immune checkpoint inhibitors (anti-PD-1/PD-L1), adoptive T-cell therapy, and chimeric antigen receptor (CAR) T-cell therapy
• Combination therapies: Integration of multiple treatment modalities, such as combining antiviral therapy with immunotherapy or targeted therapy, to enhance therapeutic efficacy and overcome resistance
• Lifestyle modifications: Promoting healthy behaviors that can reduce the risk of virus-associated cancers, such as avoiding smoking, maintaining a healthy diet, and practicing safe sex
• Public health measures: Implementing public health strategies to reduce the transmission of oncogenic viruses, such as vaccination programs, safe injection practices, and health education campaigns
• Research and development: Ongoing efforts to better understand the molecular mechanisms of viral oncogenesis, identify new therapeutic targets, and develop more effective prevention and treatment strategies