Viral Persistence, Latency, and Immune Evasion Mechanisms
Defective-Interfering Particles and Persistent Infection
1. How do defective-interfering (DI) particles contribute to persistent infections?
Defective-interfering (DI) particles are incomplete viruses that lack essential genes for full replication. They replicate only in the presence of a normal virus and compete with it for cellular resources. This reduces viral replication and cytopathic effects, allowing infected cells to survive and the virus to persist long-term.
Viral Nucleic Acid Sensing by Pattern Recognition Receptors (PRRs)
2. Describe two PRR classes that sense viral nucleic acids and what they detect.
- Toll-like receptors (TLRs): Such as TLR3, TLR7, and TLR8, detect viral RNA inside endosomes, including double-stranded and single-stranded RNA.
- RIG-I-like receptors (RLRs): Such as RIG-I and MDA5, detect viral RNA in the cytoplasm during replication and activate interferon-mediated antiviral responses.
Reasons for Lifelong HIV Infection
3. Why does HIV infection remain lifelong? Give two reasons.
- HIV remains lifelong because it integrates a DNA copy of its genome into the host cell DNA, forming a permanent provirus.
- HIV establishes persistent infection with continuous low-level replication and immune evasion, preventing complete viral clearance.
Determinants of Viral Infection Outcome
4. What determines whether a virus causes acute, latent, or persistent infection in a specific cell type?
The outcome depends on the presence of suitable cellular receptors, the ability of the cell to support viral replication, the degree of viral cytopathic effects, and the effectiveness of the host immune response. These factors together determine whether infection is cleared, becomes latent, or persists.
Comparing Latency Forms
5. Compare EBV episomal latency with $\lambda$ phage integrated latency.
In EBV infection, the viral genome remains as a circular episome in the nucleus and expresses limited genes to maintain latency. In contrast, $\lambda$ phage latency involves integration of viral DNA into the host chromosome as a prophage, where it replicates with the host genome until induced to enter the lytic cycle.
Viral Strategies for Long-Term Host Survival
1. Compare latency and persistence in $\lambda$ phage, EBV, and HIV.
Latency and persistence are strategies that allow viruses to remain in the host for long periods.
- In $\lambda$ phage, latency occurs through lysogeny, where viral DNA integrates into the bacterial chromosome as a prophage and is replicated with the host genome. The virus remains inactive until environmental stress, such as UV radiation, triggers reactivation into the lytic cycle.
- In Epstein–Barr virus (EBV), latency occurs in B lymphocytes, but the viral genome does not integrate. Instead, it remains as a circular episome in the nucleus and expresses a limited number of genes to maintain the episome and avoid immune detection.
- HIV differs because it causes a persistent infection rather than true latency. HIV integrates its DNA into the host genome and continues low-level replication, making the infection lifelong and resistant to immune clearance.
Viral Cytopathology and Immune Influence
Explain how viruses cause cytopathology and how the immune system influences outcomes.
Viruses cause cytopathology by disrupting normal cellular processes. Viral replication can inhibit host DNA, RNA, and protein synthesis and divert cellular resources toward virus production. Accumulation of viral proteins and genomes can damage cellular structures, disrupt membranes, and induce apoptosis or cell death.
The immune system strongly influences disease outcome. Effective immune responses can clear infected cells and resolve infection, while excessive or prolonged immune responses may cause tissue damage. If the immune system fails to eliminate the virus completely, persistent or latent infections may develop.
Transmission Routes and Immunity Interaction
Explain how transmission routes interact with immunity to shape viral spread.
Transmission routes affect both viral spread and immune responses.
- Respiratory viruses spread efficiently due to frequent exposure and close contact, while mucosal immunity plays a key protective role.
- Gastrointestinal viruses must survive stomach acidity and are influenced by hygiene and gut immunity.
- Blood-borne and sexual transmission routes bypass surface defenses and often lead to systemic infection.
- Vertical transmission exposes infants with immature immune systems to severe disease.
At the population level, immunity from prior infection or vaccination reduces the number of susceptible hosts, limiting viral spread through herd immunity.
Viral Oncogenesis Requirements
Describe how viral oncogenesis occurs and why infection alone is insufficient for cancer.
Viral oncogenesis occurs when viral genes interfere with cellular control mechanisms, especially those regulating the cell cycle and apoptosis. Some viruses inactivate tumor suppressor proteins such as p53 and Rb, leading to uncontrolled cell division and cellular immortalization. Viral genomes may integrate into host DNA or persist episomally, promoting genomic instability.
However, infection alone is insufficient to cause cancer because oncogenesis is multifactorial. Host genetics, environmental factors, immune status, and accumulation of additional mutations are all required for cancer development.
Chapter 9: Latency and Persistence Differentiation
Differentiating Latent and Persistent Infections
1. Differentiate between persistent and latent infections
Persistent and latent infections differ mainly in viral activity.
- In persistent infections, the virus remains active and continues to produce viral particles at low levels over long periods.
- In contrast, in latent infections, the virus is present inside the host cell but is inactive, with no production of new viral particles except during periods of reactivation.
Characteristics of Latent Infection
2. Latent infections are asymptomatic and do not produce new viral particles
In latent infections, the virus enters a dormant state where it does not replicate or produce infectious virions. Because there is no active viral replication, the host usually shows no symptoms, and the immune system may not detect the virus until reactivation occurs.
Viral Genome Forms in Latency
3. Viral genomes in latent infections can be integrated or maintained as episomes
During latency, viral genomes can persist in two main forms.
- Some viruses, such as bacteriophage $\lambda$, integrate their DNA into the host genome, becoming part of the host chromosome.
- Other viruses, such as herpesviruses (including EBV), maintain their genome as a circular episome inside the nucleus without integrating into host DNA.
Characteristics of Persistent Infection
4. Persistent infections involve low-level viral production with minimal CPE
Persistent infections are characterized by the continuous production of viral particles at low titers over long periods. The virus causes minimal cytopathic effect (CPE), allowing infected cells to survive while still producing virus, which contributes to long-term infection and chronic disease.
Chapter 11: Viral Transmission Methods
Examples of Viral Transmission Methods
Examples of each method of viral transmission
Viruses use different transmission routes depending on their properties.
- Respiratory transmission: Includes influenza, measles, and SARS-CoV-2.
- Gastrointestinal (fecal–oral) transmission: Includes poliovirus, rotavirus, and hepatitis A.
- Sexual transmission: Includes HIV, HSV-2, and HPV.
- Blood or skin transmission: Occurs through needles or transfusions and includes HIV and hepatitis B and C.
- Eye (conjunctival) transmission: Occurs accidentally and includes adenovirus and HSV-1.
- Vector-borne transmission: Occurs through insects and includes yellow fever and dengue viruses.
Vector-Borne, Zoonotic, and Spread Metrics
4. Vector-borne viruses (arboviruses)
Vector-borne viruses are transmitted by arthropods such as mosquitoes and ticks and are called arboviruses. Transmission occurs when an insect feeds on an infected host and transmits the virus to another host during a bite. Examples include yellow fever, dengue, and Zika viruses.
5. Zoonotic infections and dead-end
Zoonotic infections are transmitted from animals to humans, where humans are not the natural host, such as rabies and HIV. In dead-end infections, humans become infected but the virus fails to spread efficiently to other humans because it is poorly adapted for human-to-human transmission.
6. Infectivity and contagiousness
Infectivity is measured at the individual level by $\text{CID}_{50}$, which is the dose required to infect 50% of individuals; a lower $\text{CID}_{50}$ indicates higher infectivity. Contagiousness is measured at the population level by the basic reproduction number $R_0$, which represents the average number of new infections caused by one infected individual.
Chapter 15: Immunotherapeutic Advances
Immunotherapeutic Advances Employed Against Infectious Disease
1. T-cell engineering
T-cells are taken from the patient and genetically changed so they can better recognize infected or abnormal cells. These modified T-cells are returned to the body and can kill diseased cells directly, without needing MHC.
2. Activation of lymphocytes
This method strengthens the immune system. Vaccines create immune memory, checkpoint inhibitors remove immune suppression, cytokines increase T-cell activity, and bispecific antibodies help immune cells attach to diseased cells.
3. Antibody based therapy
Monoclonal antibodies are used to bind to viruses or infected cells, which helps block infection or destroy the infected cells.
Monoclonal Antibodies and Cytokine Storm Management
Monoclonal Antibodies Against ZIKA and SARS-CoV-2
Monoclonal antibodies against Zika virus work by binding to viral entry receptors, preventing the virus from attaching to and infecting host cells. In SARS-CoV-2 infection, excessive activation of macrophages and T-cells leads to high levels of IL-6, causing a dangerous cytokine storm. The anti-IL-6 monoclonal antibody Tocilizumab has shown effectiveness in reducing this severe immune response in patients.
Bispecific antibodies
They bind simultaneously to a ligand on a T cell and an antigen on an infected or diseased cell. This physical linkage brings the immune cell close to its target and directly activates the lymphocyte to kill the infected cell.
Cytokine storm occurs when there is excessive cytokine release due to overactivation of immune cells, which can damage tissues and worsen disease. Monoclonal antibodies, such as anti-cytokine antibodies, are used to reduce cytokine levels and lower viral impact in the body.
Chapter 10: The Viral Decision Game
Lytic vs. Lysogenic Pathways
Activity Included: The Viral Decision Game: Lysogeny or Lytic?
This activity illustrates how viruses, particularly bacteriophage $\lambda$, make a regulatory decision between entering the lytic or lysogenic pathway. The decision depends on viral gene expression and host conditions, highlighting that viral replication is not automatic but tightly regulated by molecular signals and environmental cues.
Possible Outcomes of Infection: Lytic Cycle and Lysogenic Cycle
After infection, a virus can follow either the lytic cycle, where viral genes are expressed, new virions are produced, and the host cell is lysed, or the lysogenic cycle, where the viral genome integrates into or persists within the host genome without killing the cell. In lysogeny, the virus remains dormant and is replicated passively with the host DNA.
Lytic vs Lysogenic Cycle Details (Bacteriophage $\lambda$)
Lytic vs Lysogenic Cycle (Bacteriophage $\lambda$)
After infection, bacteriophage $\lambda$ can follow either the lytic cycle or the lysogenic cycle. In the lytic cycle, viral genes are expressed, new phage particles are produced, and the host bacterium is lysed. In the lysogenic cycle, the viral genome integrates into the host chromosome and remains dormant as a prophage, replicating passively with the host cell without causing cell death.
2. Role of the CII Protein in the Lytic–Lysogenic Decision
The CII protein is the key regulatory factor that determines whether bacteriophage $\lambda$ enters the lytic or lysogenic cycle. When CII is stable and present at high levels, it activates promoters that favor lysogeny. However, when CII is degraded by host proteases, lysogeny is not established and the virus proceeds into the lytic cycle. Thus, host conditions strongly influence viral fate through CII stability.
3. Key Genes and Promoters in the Lytic and Lysogenic Cycles
In the lytic cycle, transcription from the $P_L$ and $P_R$ promoters leads to expression of genes such as cro, N, and Q, which promote viral replication and late gene expression. In contrast, lysogeny is promoted by activation of the $P_{RE}$ and $P_{int}$ promoters, resulting in production of the CI repressor, which inhibits lytic genes, and integrase (Int), which allows integration of the viral genome into the host DNA.
4. Circularization of $\lambda$ DNA via cos Sites
After entering the host cell, bacteriophage $\lambda$ linear DNA undergoes circularization, which is essential for both replication and lysogeny. This process is facilitated by cos sites, which are short complementary single-stranded sequences at the ends of the viral genome. These sequences anneal and are sealed by host DNA ligase to form a circular DNA molecule.