Viral Pathogens II

Question 1

1. During the acute phase, whilst HIV RNA is increasing what is subsequently decreasing?

Answer 1

The T-Cells

Question 2

2. When would the HIV RNA peak?

Answer 2

• The HIV RNA peak occurs at 6 weeks after which it decreases (clinical latency) until many years later when opportunistic infections cause the RNA levels to increase.

Question 3

3. What happens in a typical untreated patient of HIV?

Answer 3

o In a typical untreated patient, ten billion virions are made and destroyed every day during the chronic phase of a disease.
o The inexorable (cant stop) depletion of CD4 T cells during infection ultimately leads to immunodeficiency (AIDS) and mortality (via opportunistic infections).

Question 4

4. What is a trait of the HIV virus that is evolutionary beneficial?

Answer 4

•This long infection period is evolutionary beneficial to the virus because it gives the virus longer for transmission.

Question 5

5. What is viral load and how can we determine it?

Answer 5

Viral load is the number of Viral RNA genomes per ml of blood
Determined by PCR

Question 6

6. Explain what you would see on a graph of the levels of T cells/CD4 and Viral load against time?

Answer 6

AT first T cells will start to decline whilst HIV RNA increases ( primary infection)

At around 6 weeks the HIV RNA will reach a peak level and then decline (Clinical Latency-lasts years) T cells may increase slightly but then decrease slowly - due to this decrease there is onset of symptoms- years later

Opportunistic infections cause the HIV RNA to increase again and T cells to majorly decline - results in DEATH

Question 7

7. Why is it important for the virus to invade the immune response?

Answer 7

•Viruses must evade immune responses because immune cells recognise and kill cells infected by virus.

Question 8

8. How does the virus evade the immune cells?

Answer 8

• To evade this type of immune response, some viruses replicate in the immune cells whose function is to recognize and kill infected cells.
• Replication in immune cells hides the virus from immune cells and inhibits immune cell function.
• Inhibition of immune cell function allows other pathogens to replicate in virus infected hosts and, thus, disease occurs - Opportunistic infections of HIV associated pathogens.

Question 9

9. T cells can be either permissive or non-permissive. What does this mean?

Answer 9

•Permissive T-cells allow replication unlike non-permissive cells (certain replication stages can’t be completed).

Question 10

10. What happens in permissive T cells?

Answer 10

In permissive cells, once the virus has replicated its genome into dsDNA. This DNA enters the nucleus and is recognised as non-self, this causes caspase-3 activation which triggers apoptosis (cell death).
o For the most part, the virus will shut down/evade this immune response to virus replication but some cells (small numbers) will die.

Question 11

11. What happens in non-permissive cells?

Answer 11

In non-permissive cells, full viral replication doesn’t occur however the viral RNA/DNA is detected as non-self by IFI6 DNA sensor. This activates the innate antiviral and inflammatory responses as well as inflammasome assembly (multiprotein complex that activates highly pro-inflammatory cytokines). This results in the activation of caspase-1 which results in pyroptosis (cell death and excretion of immune factors that results in more inflammation).

Question 12

12. What are the effects of pyroptosis ?

Answer 12

• HIV infection causes pyroptosis which release cellular contents and pro-inflammatory cytokines which causes inflammation. Inflammation brings new T-cells to infect and destroy in a positive feedback cycle.

Question 13

13. How is there HIV independant cell death ?

Answer 13

•HIV independent: Uninfected cells migrate into the area due to inflammatory factors and undergo cell death resulting in more inflammation.

Question 14

14. What is the effects of the death of immune cells?

Answer 14

•This constant activation (over-charges) causes immunodeficiency which makes you susceptible to opportunistic infection.

Question 15

15. What are some HIV associated pathogens?

give eg of a virus, bacteria,fungus and parasite?

Answer 15

• Virus: Herpes simplex virus (HSV) or Kaposi’s sarcoma herpesvirus (KSHV).
• Bacteria: Mycobacterium tuberculosis (TB) or Salmonella.
• Fungus: Candida or Cryptococcus neoformans.
• Parasite: Cryptosporidium or Toxoplasma gondii.

Question 16

16. What is AIDS?

Answer 16

• Reactivation of oral/genital/anal Herpes Simplex Virus and Human Herpes Virus 8 in Kaposi’s Sarcoma.

Question 17

17. What are the two possible routes of infection of AIDS?

Answer 17

primary infection and reactivation from latency.

Question 18

18. How can primary infection be resolved?

Answer 18

• Primary infection can be resolved (typically by immune suppression) - Infection moves to sites in the host that the immune system does not access where they stay latent (resides without replicating).

Question 19

19. Why would there be reactivation from latency?

Answer 19

•Reactivation from latency occurs upon immunodeficiency (no immune suppression to dampen the virus).

Question 20

20. Explain how HSV becomes latent and they gets reactivated?

Answer 20

• The virus replicates in the infected epithelial cells and then moves into the nervous system which has poor immunosurveillance due to most immune cells not crossing over the blood-brain barrier.
• The virus then moves along neurons into the CNS where it sits in latency until there is immunodeficiency.
• Normally, continuous immunosurveillance sends signals to the virus. When this signal is removed the virus is reactivated from latency and travels back to the infection site.

Question 21

21. What is KSHV ?

Answer 21

Kaposi’s sarcoma-associated herpesvirus

ie Oncogenesis of Kaposi’s Sarcoma (cancer/) associated with HIV and AIDs

Question 22

22. What is A celll(A type KSHV?

Answer 22

• A: Asymptomatic KSHV infection in a healthy individual:
o The virus infects cells produces KS progenitor cells which is known as de novo (primary) infection which can lead to latent infection e.g. in a B cell or a lytic immunogenic response (destroys immune cells).
o The latent infection can be reactivated to enter the lytic cycle in response to a cue e.g. a T cell.
o The immunogenic response can lead to reinfection.

Question 23

23. What is B cell KSHV?

Answer 23

• B: Viral Oncogenesis of AIDS-Kaposi’s sarcoma:
o Some types of B-cells are permissive, and some are non-permissive for oncogenesis.
o Re-activation from latency into the lytic cycle by cues such as inflammatory cytokines. Some of these cells become oncogenic and undergo uncontrolled cell division.
o During the uncontrolled division, an inflammatory reaction occurs in KS legions which produces more inflammatory cytokines etc for latent reactivation.
o ART (anti-retroviral therapy) stops HIV replication which stops the inflammatory response.
o Gancyclovir (direct acting anti-viral drug) prevents KSV replication in B cells and other cells.

Question 24

24. What are some viruses that cause cancer?

Answer 24

• Human papilloma viruses (HPVs) – Papilloma virus, circular dsDNA genome, skin cancer.
• Epstein-Barr virus (EBV) – Herpes virus, linear dsDNA genome, lymphoma.
• Hepatitis B virus (HBV) – Hepadnavirus, circular dsDNA genome, carcinoma.
• Hepatitis C virus (HCV) – Flavivirus, ssRNA genome, carcinoma.
• Human herpes virus 8 (HHV-8) - Herpes virus, linear dsDNA genome, lymphoma.
• Human T-lymphotrophic virus-1 (HTLV-1) – Retrovirus, RNA-DNA genome, leukemia/ lymphoma.
• Merkel cell polyomavirus (MCV) – Polyomavirus, dsDNA genome, carcinoma.