W21 Viral infections, oncoviruses and antiviral chemotherapy

Question 1

What needs to be done for a virus to cause disease?

Answer 1

a. Infect their specific host’s cells
b. Replicate efficiently within the host
c. Damage targeted tissues

Question 2

What is Viral pathogenesis?
What are the 3 requirements for a successful infection?

Answer 2

=The process of a virus producing a disease
* Enough virus
* Accessible Cells that permits the viral replication
* Local antiviral defense/immune system absent or overcome

Question 3

What is an Asymptomatic infection?

Answer 3

Most virus encounters have no consequence
Many infections are inapparent or asymptomatic

Question 4

What is an acute infection?

Answer 4

• Viruses can cause acute infections
  -Display short incubation periods upon virus entry
  into the host.
  -Rapid onset of disease
  -Brief period of symptoms
  -Quick resolution (elimination of virus by the immune system)

Question 5

Clinical manifestations (physical result of an infection) can be due to:

Answer 5

1. Genetic factors
2. Age
3. Comorbidity (other diseases)
4. Individual immune response

Question 6

What is a Latent infection?

Answer 6

• Latent virus remains in asymptomatic
  host cell for long periods
• No symptoms or viruses are detectable/active
• May reactivate due to changes in immunity
• Cold sores (e.g. herpes simplex virus, HSV-1),
  shingles (varicella zoster virus, VZV)

Question 7

What is a Persistent/Chronic infection?

Answer 7

• A persistent viral infection occurs
  gradually over a long period;
• Hepatitis B virus (HBV )infection, where the
  virus continue to replicate over time a low level
• Not all HBV infections become chronic

Question 8

Herpesvirus – latency
What is produced during the primary infection? (2)

Answer 8

Herpes simplex viruses (HSVs) and varicella-zoster virus (VZV) remain latent in a quiescent but persistent form (latent infection), in neural ganglia cells

• Primary infection occurs producing
  -Cold sore usually for HSV-1
  -Chicken pox for VZV
• Infections produces progeny virions that spread elsewhere
• Virus enters innervating sensory neurons, and viruses are transported to the neuronal cell body.
• Viral DNA is released into the neuronal nucleus
  and circularizes (episomal state)
• Circular viral DNA persists in the neuronal cell
  nucleus

Question 9

Herpesvirus – reactivation
What is HSV-1?

Answer 9

• HSV-1 can periodically reactivate to cause cold sores, in response exposure to sunlight, psychological stress, fever, menstruation and surgical resection
• Reactivation in the neuronal cell body
• Newly formed capsids are transported to the axonal termini.
• Infectious virus is released from the axon and infects epithelial cells, resulting in recurrent infection and virus shedding.

Question 10

What are viruses that are known to cause cancer called?
What do they do?

Answer 10

Oncoviruses
-Most of them (not all), become integrated into the host cell’s DNA and induce tumours

Question 11

What is meant by
Unregulated cell proliferation?
Genetic/chromosome instability?

Answer 11

= Cell cycle/division is always on
= Mutations accumulation in many genes

Question 12

When does cancer caused by viruses develop?
Are they contagious?

Answer 12

• May develop long after a viral infection
• Cancers caused by viruses are not contagious

Question 13

Functions of oncoviruses

Answer 13

1. Encode proteins that act as oncogenes themselves
2. Activate cellular proto-oncogenes (normal) to oncogenes (hyperactive) - different ways
3. Inactivate tumour suppressor genes
   * Cell cycles are no longer regulated at checkpoints (in a normal conditions, If conditions are not right, cell cycle pauses at checkpoints)

Question 14

Viruses have been implicated in the genesis of cancers:
(for info)

Answer 14

Contributes to around 20% of human cancers
e.g.
1. Human papillomaviruses (HPV) – Cervical cancer (MAIN ONE*), Head and Neck Cancers, Anal, Oral, Pharyngeal, and Penile Cancer
2. Human T-cell lymphotropic virus I (HTLV-1) – T cell leukemia

Question 15

Isolation and Cultivation of Viruses:
How do scientists propagate viruses in different systems? (3)

Answer 15

1. Animals (used only before the tests of drugs/vaccines on humans)
2. Embryonated eggs
3. Cell cultures (cell suspended in culture medium)

Question 16

Isolation and Cultivation of Viruses (For info)

Answer 16

• Cell are prepared to grow in plates similar to Petri dishes and sample containing viruses are added to allow virus to attach to the cells and then removed
• Cell are then covered with Agar or other reagents to block the diffusion of viruses. Virions progenies produced by a single cell could only infect surrounding cells.
• As result, there will be localised area of cell destroyed (viral plaques) and detected by using a dye to stain just the viable cell. The dead cells of the plaque do not retain the dye.
• Each plaque corresponds to an area of cells infected and dead by single virus; expressed as plaque-forming units (PFU)

Question 17

Why are vaccines given?
What will they protect people against?

Answer 17

=Vaccines are predominantly used to prevent viral infections/severe diseases.

Establish a protection in immunised people which will protect them from:
1. A possible infection and/or subsequent illness when they come into contact with the respective pathogens
2. Many technologies available to develop vaccines (e.g. providing dead/attenuated viruses or proteins or mRNA to trigger a specific immune response)
3. Some viral diseases, often deadly have been eradicated (e.g. Smallpox) or almost eradicated (e.g. Poliomyelitis caused by poliovirus)

Question 18

Antiviral drugs
Antiviral chemotherapy to treat specific viral infections:
How do they work?

Answer 18

• A drug interfering specifically and selectively
  with the virus replication (effective) with no/low
  effects on the host cell activity (viable and safe).
• Inhibiting an essential step of the viral life cycle
• Used to treat infections of specific virus, according to the related target/mechanism of action
• Importance of the mechanism of action as no-
  broad spectrum antiviral is currently available.

Question 19

Human Immunodeficiency Virus (HIV)

Answer 19

Common characteristics of viruses:

-HIV belongs to the Retroviridae family, classified into
two subtypes: HIV-1 and HIV-2. HIV-1 is more virulent
and more infective.
-Viruses that insert a copy of its RNA genome into the host cell’s genome (lifespan chronic infection).
-HIV causes acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune system (decreasing CD4+ T-lymphocyte count) allows life-threatening opportunistic infections (e.g. Criptococcus) and cancers (oncovirus) to thrive.

Question 20

What are the 3 stages in the progression of HIV infection?

Answer 20

1. Acute HIV: flu-like symptoms that occur days to weeks after contracting HIV.
2. Chronic HIV: the latent and asymptomatic
   stage that can last several years.
3. AIDS: occurs when CD4 cell count falls below 200 cell/mm3. This makes people vulnerable to opportunistic infections and AIDS-defining conditions.

If HIV infection is not treated, the median time from infection to the development of AIDS is 8-10 years. HIV infection needs to be treated.

Question 21

HIV Combinational therapy (cART/HAART)

Answer 21

The highly active antiretroviral therapy
(HAART): treatment regimen typically
comprised of a combination of
two/three antiretroviral drugs with
different mechanisms of action

Different mutations are required to
develop drug resistance to all drugs
 Reduced risk of drug resistance
Principle of combination therapy:
Combining different antiviral drugs with distinct mechanisms of action having
a proved synergistic activity against HIV

Question 22

HIV Combinational therapy (cART/HAART)

What are the goals of HAART in patients with HIV infections? (4)

Answer 22

1. Reduce plasma viral RNA to an undetectable level
2. Prevent or reduce drug resistance
3. Reduce morbidity and mortality
4. Prevent HIV transmission
   Undetectable = Untransmittable

HAART does not cure HIV infection (cannot eradicate/clear the virus from an infected
individual), due to the establishment of latency (viral genome is integrated into the human genome