16: Persistant Infections

Question 1

What is a persistent infection?

Answer 1

• primary infection is not cleared by immune response
• virus particles, proteins and genome continues to be produced
• No single mechanism
• Tends to happen with viruses with minimal cytopathic effects
• Viruses are good at immunomodulation

Question 2

How do viruses cause persistent infections modulate/evade the immune system?

Answer 2

Cytotoxic T cells (CTL)

1) Immunomodulation by targeting MHC class 1 mediated by Ag-presentation pathway, thus preventing the activation of CTL

2) Reduced immune surveillance in some organs:

• cells/organs differ in the degree of immune defences
• some tissues such as CNS and vitreous humour of the eye devoid of initiators and effects of immune response
• these issues cannot afford fluid accumulation, swelling and tissue damage induced by inflammation
• persistent infections of these organs are common

3) Infection of immune cells

• many viruses infect immune cells, thus suppressing the immune system leading to the persistence of infection
• Measles infect APCs
• HIV infects CD4 T cells

Question 3

What is HIV? Human immunodeficiency Virus

Answer 3

Family: Retroviridae
Subfamily: Orthoretrovirinia
Genus: Lentivirus

HIV-1
- Bovine immunodeficiency virus
- Caprine arthritis encephalitis virus
- Equine infectious anemia virus
- Feline immunodeficiency virus

HIV-2
- Jembrana disease virus
- Puma lentivirus
- Simian immunodeficiency virus (SIV)
Visna-maedi virus

Question 4

What is the source of HIV-1?

Answer 4

zoonotic transmission of primate lentiviruses from lower to higher primates

1921- pt 0 SIV

Question 5

What is hIV?

Answer 5

• HIV is an enveloped (+) stranded RNA viruses
  -It contains reverse transcriptase that mediates the synthesis of dsDNA copy of the viral RNA genome.
  -It contains integrase that catalyzes the insertion of viral DNA into host DNA.
• Retroviruses can be propagated as integrated elements (proviruses) that transmit in the germ line or as exogenous infectious agents.
• HIV targets CD4 T cells and it is the main cause of immune deficient syndrome pandemic.

Question 6

Are there any cures for HIV? What is the mode for transmission?

Answer 6

There is
- no cure
- no vaccine
- antiviral drugs (only slows down)
- drug resistance
- drugs are expensive

Transmission is by sex, IV, drugs and at birth.

Question 7

What is the HIV infection route?

Answer 7

• Virus crosses via erosion in the mucosal surfaces and infects CD4 T cells then…

*T cells transfer virus particles to lymph nodes (LN) and gastrointestinal-associated lymphoid tissue (GALT)

*Active viral replication in LN results in high viremia and systemic dessimination

*DCs and langerhans cells (LC) play a role in delivering the virus to LN

Question 8

How does HIV attach and enter?

Answer 8

Attachment
- Primary receptor: CD4
- Co-receptor: Chemokine receptor CCR

Entry: gp 120 AND CCR-CD4 interaction leads to conformational changes In gp41 protein and it exposes the fusion peptide and permits its insertion into the plasma membrane which catalyzes fusion and releases its viral genome into the cytoplasm

Question 9

What is the HIV infectious cycle?

Answer 9

1. Attachment and Fusion: The virus binds to cell surface receptors via its envelope protein and fuses with the cell membrane, releasing the viral core into the cytoplasm.
2. Reverse Transcription:
   The viral RNA genome is converted into double-stranded DNA by reverse transcriptase (RT) within the viral core.
3. Nuclear Entry:
   Viral DNA and Integrase (IN) enter the nucleus through nuclear pores.
4. Integration:
   Integrase inserts the viral DNA into the host genome, forming a provirus.
5. Transcription: Host RNA polymerase transcribes the proviral DNA into full-length RNA.
6. RNA Processing:
   Full-length RNA is used as mRNA or as genomes for new viruses. Some RNA is spliced to produce envelope (Env) protein mRNA.

7 Translation: mRNAs are translated into viral proteins (Gag, Gag-Pol, and Env) by cytoplasmic and ER-associated ribosomes.

8. Protein Processing:
   Env glycoproteins are modified in the Golgi and transported to the cell surface.
9. Assembly and Budding: Viral components (RNA, Gag, Gag-Pol, and Env) assemble at the plasma membrane and bud off, forming new viral particles.
10. Maturation: Viral protease cleaves precursor proteins, resulting in mature, infectious viruses.

Question 10

Progress of HIV Infection

Answer 10

*Acute phase (0-11 weeks):
- Swollen lymph nodes
- Fever
- Diarrhea

Cellular Level :
- CD4+ T cells decline temporarily
- CD8+ cells increase temporarily

*Chronic phase (1-8 yrs)
- no symptoms

Cellular Level (1-8 yrs) :
- CD4+ T cells decline gradually
- CD8+ cells unaffected

Symptomatic phase: AIDS 8-12
- 200-500 cd4+ cells
- oral/skin lesions
-genital warts

Cellular level:
- CD4+ cell gone, loss of helper function
- HIV-1 specific CD4+/CD8+ cell exhaustion

Question 11

HIV and cancer

Answer 11

HIV-1 infection leads to increased incidence of malignancy (40% of infected indiv. develop cancer)

Mediated by:
- Dysregulation of the immune system
- Integration of viral dna into host dna
- Absence of proper immunosurveillance

Kaposi’s Sarcoma:
- red/purple patches (skin/organs)
- tumor contains infiltrating inflammatory cells and newly formed blood vessels
- 20% men and 2% women
- Infects with herpesvirus 8 is needed for development

Other cancers:
- Lymphoma with EBV
- Skin cancer with HPV