LECTURE 10 (HIV)

Question 1

Describe HIV (Human Immunodeficiency Virus)

Answer 1

• RNA retrovirus that uses reverse transcriptase (RNA -> DNA)
• Infects CD4+ T-helper cells
• Leads to AIDS (Acquired immunodeficiency syndrome) -> Host becomes susceptible to opportunistic infections
• Natural host is humans

Question 2

How does HIV initially infect and replicate?

Answer 2

HIV enters the body (either via mucosal lesions or mucosal/cutabeous immune cells) -> attaches onto host cells with its gp120 glycoprotein -> viral envelope fuses with host cell -> capsid enters the cell

EXPLANATION: For fusion, both the CD4 receptor and coreceptor (CCR5 in macrophages, CCR5 or CXCR4 in T-cells) must be present -> viral entry into macrophages (via CCR5) occurs during the EARLY STAGES of infection, entry via CXCR4 occurs in LATER STAGES

Question 3

Which cells have CD4 receptors?

Answer 3

• T lymphocytes (e.g T helper cells)
• Macrophages
• Monocytes
• Dendritic cells

Question 4

How are some people resistant to HIV?

Answer 4

Since in order for HIV to enter the host cell it needs to bind both to the CD4 receptor and CORECEPTOR -> but, some people have a mutation in their CCR5 co-receptor -> homozygous CCR5 mutation (substantial resistance) or heterozygous CCR5 mutation (slower course)

Question 5

Describe envelope spikes of HIV that bind to CD4 cells

Answer 5

• Consist of gp120 and gp41 glycoprotein
• gp120 = outer-membrane glycoprotein
• gp41 = transmembrane glycoprotein

EXPLANATION: When the CD4 binds with gp120 it triggers multiple conformational changes in gp120 that expose and form the co-receptor binding site

Question 6

How do the receptors in HIV function?

Answer 6

In chemoattraction
[when immune cells move along gradients of chemokine molecules to sites of inflammation]

Question 7

What is the difference between R5 and X4 viruses?

Answer 7

R5 and X4 viruses form a spectrum from early transmission to late stage of HIV

R5 viruses:
- use CCR5 as co-receptor
- replicate in monocytes, macrophages and dendritic cells
- occur EARLY

X4 viruses:
- use CXCR4 as co-receptor
- replicate in T-cells
- occur LATER

R5X4 viruses:
- use both CCR5 and CXCR4
- intermediate

Question 8

Describe how infection leads to acute HIV syndrome

Answer 8

HIV infects CD4+ lymphocytes then reproduces and spreads to other CD4+ lymphocytes near the original site of infection -> infection of CD4+ lymphocytes concentrated in specialised tissue (lymph nodes + GALT) -> explosive growth and dissemination -> acute HIV syndrome with high viral load

ADDITIONAL INFO:
Window period = the time between infection and detectability of HIV bodies

Question 9

What happens after the acute phase which leads to chronic immunodeficiency?

Answer 9

Viral load decreases + remains at roughly same level for 8-10 years due to CD8+ and Cytotoxic T cells (Clinical latency stage) -> during clinical latency stage, virus replicates inside the lymph nodes whilst the immune system still tries to fight HIV -> increasing loss of CD4+ lymphocytes impairs immune function which facilitates OPPORTUNISTIC INFECTIONS and development of malignancies (AIDS) [usually cause of death in individuals with HIV]

Question 10

What are the different markers of infection?

Answer 10

• CD4 T-cell count
  [normal is around 1000 cells + AIDS is <200 + used to initiate prophylaxis against opportunistic infections]
• Viral load
  [quantification of HIV RNA + used to monitor effect of drug therapy]

Question 11

What are the symptoms of HIV?

Answer 11

• Initial infection is asymptomatic
• Acute HIV infection (2-4 weeks) = fever, myalgias, sore throat, cervical adenopathy, maculopapular rash
• AIDS (8 years) = CD4 cells < 200 cells + symptoms from opportunistic infections

Question 12

Describe the table showing the course of HIV

Answer 12

1) Initial spike of HIV RNA + rapid decline of CD4+ T cells
[Acute infection period where most patients experience flu-like symptoms]
2) CD4+ T cells somewhat recover but not as high as the level before infection + number of HIV RNA rapidly decreases
[immune system is fighting]
3) Latent period is shown by plateau phase
[HIV viruses are still replicating but are being attacked by the immune system]
4) CD4+ T cells start to deplete leading to collapse of immune system, making the person susceptible to opportunistic infections

Question 13

What does drug intervention do?

Answer 13

It can take plasma viral loads below the level of detection and prevent CD4+ T cell depletion

Question 14

Why is HIV so dangerous?

Answer 14

Since HIV infects cells of the immune system itself, activation of cellular immunity is a factor that paradoxically helps the virus spread + ensures chronic persistence of the infection

Question 15

How does HIV evade immune control?

Answer 15

• Genetic mutation and recombination
• Down-regulation of MHC class I surface molecules in infected cells