HIV and Other Immunodeficiencies

Question 1

How does HIV infect and integrate into a host cell’s genome?

Answer 1

1. The virus binds surface protein CD4 and coreceptors CXCR4/CCR5
2. When it’s inside the host cell, it releases its core shell protein around the two RNA molecules
3. The RNA molecules bind to polymerases and exit to the cytoplasm
4. Reverse transcriptase synthesises a ssDNA from the RNA template – a very unusual method
5. A DNA-RNA hybrid is made, but the RNA is degraded by ribonuclease N so that a second DNA strand can be synthesised
6. The viral information is now a dsDNA, which is imported into the nucleus and integrated into the chromosomal DNA via two ligation events that occur at the UTRs

Question 2

How is HIV activated?

Answer 2

1. Transcription factors stimulate transcription of proviral DNA into ssRNA, and after processing, several mRNAs
2. Viral RNA is exported to cytoplasm
3. Host-cell ribosomes catalyse synthesis of viral precursor proteins, which are then cleaved by viral protease, to form viral proteins
4. HIV ssRNA and proteins assemble under the host-cell membrane, where gp41 and gp120 are inserted
5. The membrane buds out, forming the viral envelope
6. Released viral particles mature; the inserted precursor proteins are cleaved by viral protease present in the virus particle

Question 3

What is the difference between latent and active HIV infection?

Answer 3

Latent HIV infection

• No damage is caused
• The virus is undetectable because it has not produced any viral proteins, and therefore, cannot be eliminated

Active HIV infection

• Damage is caused as viral proteins have been produced and released
• Can be detected and marked for destruction by the immune system

Question 4

Describe the HIV genome and proteins.

Answer 4

Complex retroviruses

Have three major genes (gag, pol, env)
- Encode for polypeptide precursors that, when cleaved, yield nucleocapsid proteins (required for replication) and envelop proteins

The remaining six genes
- Regulate HIV transcription, RNA transport, virus assembly and release from cell, and immune evasion

LTRs
- Integrate the DNA copy of viral genome into the host chromosome

nef

• Reduces MHC expression, making it harder to detect by CTLs
• After entry into the host cell, reduced expression of cellular proteins (CTLA-4 and CD4) which help it enter the cell

Question 5

Describe the four main mechanisms by which HIV-infected cells die.

Answer 5

1. Virus-induced cell death: The virus recklessly exhausts the cell’s resources through large viral production
2. CD8+ CTL-induced killing: CD8+ CTLs kill HIV-infected cells and recognise other T cells as infected, lysing it or instructing its self-destruction
3. Syncytia formation: gp120 on infected cells binds to CD4 on uninfected cells, leading to cell fusion (one big cell with two nuclei and one gp120 on the surface)
4. Bystander effect: Infected cells do not produce new virus particles due to incomplete reverse transcripts; still activates innate immune responses and induced apoptosis

Question 6

Describe the typical course of an untreated HIV infection.

Answer 6

Acute Phase:
Exponential viral growth as the viruses are unaffected by early immune responses

After 6 Weeks,
Virus numbers drop but not to zero as some viruses survive the onslaught of immune responses by staying latent

Over Time,
The immune system induces immune responses but with progressively decreasing strength due to decrease in CD4+ CTL numbers

Question 7

What are the targets for therapeutic antiretroviral drugs that inhibit HIV replication?

Answer 7

1. Binding of coreceptors CXCR4/CCR5 to Env spike
2. Viral fusion with membrane
3. Copying of viral RNA chromosome into cDNA by viral reverse transcriptase
4. Insertion of viral double-stranded cDNA into host chromosome via viral integrase
5. Processing of large viral precursor proteins into mature viral proteins by viral protease

Question 8

PrEP vs PEP

Answer 8

PrEP (Pre-exposure Prophylaxis)

• Taken everyday before possible HIV exposure
• By people who don’t have HIV but have a sex partner with HIV, have sex with people with unknown HIV status, and share injection drug equipment
• Reduce the risk of getting HIV from sex and injection drug use

PEP (Post-Exposure Prophylaxis)

• Taken in emergency situations after possible HIV exposure (within 3 days)
• Taken by people with the same risk factors
• Can prevent HIV infection when taken correctly, but not always effective