11 - Effects on Host Cell

Effects of Infection on Cell Cycle and Cell Death
- Overview of how infections influence cellular processes.
- Related to biological implications in the context of virology and cancer.
- Context: Lecture 11, BIOL 41600, Spring 2025.

Virus Association with Cancer Incidence
- Flavivirus: 600,000 global annual incidences.
  - Virus: Hepatitis C (HCV).
  - Tumor: Hepatocellular carcinoma.
  - Cofactors: None.
- Hepadnavirus (including HCV):
  - Hepatitis B (HBV) induces similar tumors with cofactors: alcohol, smoking.
- Herpesvirus (~70,000 in the US/year):
  - Associated viruses: Epstein-Barr virus causes several lymphomas including Kaposi’s sarcoma, nasopharyngeal carcinoma, and gastric cancers.
  - Malaria serves as an immunodeficiency cofactor (HIV).
- Papillomavirus:
  - 20% of all women have precancerous cervical changes.
  - 11,000 cervical cancer diagnoses annually with a fatality count of 4,000.
  - Causes cervical and ano-genital tumors; linked with skin cancer and potential UV exposure.
- Retroviruses (including EBV):
  - HTLV-I, HTLV-II associated with Adult T-cell leukemia/lymphoma.

Proto-oncogenes:
- Trigger progression through the cell cycle.
  - Functions include releasing E2F from Rb and inhibiting cell death.
  - Activation leads to cell division.
Tumor Suppressor Genes:
- Trigger halting of the cell cycle.
  - Functions to keep E2F bound to Rb and promote cell death.
  - Deactivation leads to cell division.
Growth Factor Signaling:
- Induces terminal differentiation and responds to DNA damage signaling.
Viral Implications:
- All virus-induced transformations alter expression or function of proto-oncogenes, tumor suppressors, or both.

Nature of Viral Cancer:
- No virus life cycle is dependent on tumorigenesis.
- Tumorigenic viruses aim to replicate/spread, not to cause cancer.
- Types of infections:
  - Permissive: Causes cell death.
  - Non-permissive: Immune system often eliminates infected cells via apoptosis.
- Dead cells cannot become tumors; cancers result from abnormalities in host or virus.

Viral Factors:
- Loss of genes essential for replication but retention of genes that trigger cell division.
Host Factors:
- Infection by a non-replicating virus that affects cell cycle progression.
- Mutations in tumor suppressor genes (cofactors).
- Immune suppression hindering elimination of infected cells.

Two Types:
- Unintentional Perturbation of Cell Cycle:
- Intentional Perturbation of Cell Cycle:

Viral Oncogenes:
- Play no role in the virus lifecycle; three types:
  1. Transduce a mutated cellular proto-oncogene.
  2. Upregulate an endogenous cellular proto-oncogene (non-transducing).
  3. Inactivate a cellular tumor suppressor.

Historical Discovery:
- 1916: Peyton Rous discovered the first oncogenic virus (Rous Sarcoma Virus).
- 1970: Steven Martin finds part of the nucleic acid of the virus is sufficient to transform cells.
- 1976: Research by Varmus and Bishop leads to understanding that oncogenes are captured cellular genes (Nobel prize 1989).
Transformation Mechanism:
- v-src is a captured gene associated with cellular proliferation.

v-Src:
- A captured cellular gene associated with persistent activation of cell proliferation signals.
Comparatively, c-Src is a tyrosine kinase required for transducing signals.

Mechanisms:
- Alter the expression of endogenous proto-oncogenes such as myc.
  - Increases transcription factors which drive overexpression during the G1 phase.
- Viral mutations can lead to constitutive expression of oncogenes.

Implications:
- 20% of human cancers are virus related, but caused by non-transducing retroviruses.
- Examples of cancer related to retroviral gene therapy include cases of X-linked Severe Combined Immune Deficiency in children, resulting in clonal leukemia post-treatment.

Mechanism:
- Viral oncogenes actively alter the cell cycle for replicative advantage; two categories:
  - Defective Viruses (adenovirus, polyomavirus, papillomavirus).
  - Latent Viruses (herpesvirus).

Mechanisms of Action:
- Growth Signals: Kinase cascades activate signaling pathways for cell cycle progression.
- Tumor Suppressor Functions: Inhibition of cell division through pathways associated with Rb and p53.
- Tumor Induction: Viral proteins aim to disrupt these regulatory processes for propagation.

Key characteristics of oncogenic viruses include their integrations, cloning characteristics, and defectiveness in virions.
Virus-induced transformation paths:
- Include transducing, nontransducing actions, and direct DNA viral interference with tumor suppressors.

Definition: Genetically programmed cell death regulated by intrinsic or extrinsic signals.
- It involves caspase activation leading to cellular disassembly.
- Critical for removing damaged or unnecessary cells.

Caspase Activation: Two key pathways (intrinsic and extrinsic) converge at executioner caspases.
- Intrinsic pathway involves mitochondrial signaling, extrinsic involves death receptors.
Regulation: Members of the BCL-2 family play critical roles in mitochondrial regulation and cell survival/death decisions.

Mechanisms by RNA and DNA Viruses:
- RNA viruses primarily induce via cell stress mechanisms affecting protein synthesis.
- DNA viruses often result in unscheduled cell division leading to activation of apoptotic pathways.

Viral Proteins: Mechanisms used by various viruses to inhibit apoptosis include mimicking cellular pathways or directly inhibiting caspase functions.
- Example includes baculovirus and its proteins which target caspases.

Importance of Understanding Apoptosis:
- Apoptosis is crucial for maintaining cellular health and is influenced by viruses.
- DNA viruses have developed strategies to inhibit these pathways, contributing to their survival.