Lecture 6/7-Human Viruses & Disease

Asymptomatic

Infection that does not lead to disease

How does infection occur?

Virus enters a host and multiplies

When does Disease Occur?

host’s body cells are damaged as a result of infection and signs/symptoms of an illness appear

Immune Symptom

• Activated in response to infection

• signs/symptoms of disease result from immune system activity

Viral Virulence

Capacity of a virus to cause disease in a host

Virulent Virus Strain

causes significant disease

Avirulent/Attenuated Virus

causes no or reduced disease

Animal Models for Virus Study

• Animal viruses that resemble human infection

• Human viruses in animals

Plaque Assay

a technique to measure virus titer (determining the quantity of infectious virus) and to biologically clone a virus

Virus Propagation Allows

• Vaccine development by providing viral antigens

• Greater knowledge about virus lifecycle

• Greater knowledge about virus pathogenicity

• Anti-viral drug development

Measuring Virulence

• Virus Titer

• Mean time to death

• Mean time to appearance of signs

• Measurement of fever/weight loss

• Measurement of Pathological Indicators

• LD50

• ID50

Virus Titer

measures the concentration of infectious or total virus particles in a sample

LD50

Lethal dose for 50% death

ID50

infectious dose for 50% symptoms

Kaplan-Meier Curve

a step-plot graph that visualizes the probability of an event (e.g., survival, disease relapse) over time

Factors Influencing Viral Virulence

• Dose

• Route of infection

• Species

• Age

• Gender

• Susceptibility of host

• Social factors

• Economic factors

Genetic Determinants of Viral Virulence

Major goal of virology

Discovering Genetic Determinants of Viral Virulence

• Usually identified by mutation

  • A virus that causes reduced/no disease in a specified system

Viral Virulence Genes May

• Affect ability of the virus to replicate

• Enable the virus to spread within a host or between hosts

• Defeat host defence mechanisms

• Have intrinsic cell killing effects

Cross-species Virus Transmission and Virulence (Increase)

Cause of some of the most devastating epidemics and is associated with an increase in virulence

• ex: jump of SIV and non-human primates to HIV in humans

Cross-species Virus Transmission and Virulence (No Change)

No apparent change in virulence following a host jump

• ex: Influenza A virus H3N8 that jumped from horses to dogs

Cross-species Virus Transmission and Virulence (Decrease)

Often overlooked

• ex: decreased virulence when infectious haematopoietic necrosis virus spread from salmon to trout

Pathogenesis

the process by which virus infection leads to disease

Disease occurs only if the virus replicates sufficiently

• Damage essential cells directly

• cause the release of toxic substances from infected tissues

• damage cellular genes

• damage organ function indirectly as a result of the immune response to the presence of virus antigens a

Cytolytic Viruses

Causes the most productive infections because they kill the host cell

Cytopathic Effects (CPE)

Changes in cell morphology caused by infecting virus

Virus vs Host

Speed of virus replication and spread vs location/timing/magnitude of the summe response = outcome of viral infection

Acute Infection

high but transient viral replication

Acute Replication

• Rapid onset of viral replication

• Short but possibly severe course of disease

• Production of large numbers of virus particles

• Immune Clearance

Examples of Acute Infection

• Influenza A Virus (IAV)

• SARS-CoV2

• Polio Virus

• Measles Virus (MeV)

• Ebola Virus (EBOV)

• Variola Virus

Chronic/Persistent Infection

continuous productive infection and/or latency and reactivation

Patterns of Viral Infection and Disease

Continuous Reproductive Replication

• Continuous regeneration of infectious virus despite ongoing antiviral immunity

• Continuous stimulation of immune system due to continuous expression of viral proteins

• Generally non-cytopathic viruses: low levels of cell death/tissue damage

Examples of Continuous Reproductive Replication

• HIV

• HCV

• HPV

• EBOV

• MeV

• ZIKV

Latent Infection and Reactivation

• Viruses go into transcriptionally and antigenically silent state

• Intermittently reactivate to generate new infectious virus

• No known immune mechanism to clear latent virus-infected cells

Examples of Latent Infection and Reactivation

• HIV

• HCMV

Major Viral Strategies for Persistent Infection

• Selection of cell subsets

• Modulation of viral gene expression

• Subversion of cellular apoptotic pathways

• Avoidance of the immune system

Selection of Cell Subsets

Some cells can serve as sanctuaries for a persistent infection

• Ex: neurons (MeV) and memory T-cells (HIV) —> live a long time

Examples of Selection of Cell Subsets

• MeV: Established chronic infection in neurons, ling-lived cells in the central nervous system (CNS)

• HIV: Established a latent infection in the resting memory CD4+T cells, long-lived cells of the immune system

Modulation of Viral Gene Expression

Ensures survival of the host cell if the virus is cytopathic and to avoid immune recognition

Example of Viral Gene Expression

Chromatin Modification

Subversion of cellular apoptotic pathways

During acute infection, a virus needs to prevent apoptosis of infected cells to keep them around longer

Example of Subversion of Cellular Apoptotic Pathways

Viruses inhibit the activity the cellular pro-apoptotic p53 protein

Avoidance of Clearance by the Immune System

• RNA viruses exploit genetic variability to avoid recognition by the immune system

• High mutation rate in RNA Viruses

• Multiple escape mutants enable the virus to evade the immune response

Interferon Response

HCV Blocks in IFN Induction Pathway

• HCV NS3/4A protein complex acts as a viral interferon antagonist.

• NS3/4A proteolytically cleaves MAVS.

• Cleavage of MAVS blocks the downstream signaling cascade and stops interferon expression

HCV Blocks IFN Signalling Pathway

• HCV core protein acts as a viral interferon antagonist.

• Core inhibits STAT1 phosphorylation and, therefore, its activation.

• Core also induces STAT1 degradation.

• Inhibition of STAT1 prevents downstream expression of interferon-stimulated genes (ISGs).

HCV Employs Multiple Strategies to Evade the Innate Interferon Response

• Disrupts the cellular signaling pathway that leads to interferon expression.

• Disrupts the JAK-STAT pathway to limit the expression of interferon stimulated genes (ISGs).

• Disrupts the antiviral activities of ISGs

• Don’t forget that HCV also employs multiple strategies to also evade adaptive immunity.

HIV and Memory CD4+T Cells

• Infection of activated CD4+T Cells results in cell death/apoptosis

• DNA copy of the HIV genome incorporated into the nucleus of the host cell

• CD4+T Cell can get infected —> allows HIV to persist for decades, integrated into the host cell genome

How does HIV establish latency in resting memory CD4⁺ T cells?

• Accessibility of key host cell transcription factors

  • In resting memory CD4⁺ T cells, transcription factors are sequestered in the cytoplasm to suppress transcription.

  • Both host cell and HIV transcription are suppressed.

• Position of the HIV provirus in the host cell genome

  • HIV preferentially integrates into actively transcribing genes.

  • Transcription can be suppressed by transcriptional interference via proximal promoters of host cell genes

How does HIV Establish Persistent Infection?

Continuous productive replication and latency

How does HCV establish persistent infection?

Continuous productive replication in hepatocytes