Lecture 15 - HIV - Cures

Question 1

What are the differences between cure and remission?
What is the model for each?
What is the likelihood of both?

Answer 1

1. Cure: ‘infectious disease model’
   • eradication of all HIV-infected cells
   • ‘sterilising cure’
   • likely to be very difficult in HIV

2. Remission: 'cancer model'
 • long term health in the absence of cART
 • HIV still present at low levels
 • 'functional cure'
 • rare, but not impossible

Question 2

What are some unique cases of cure of HIV?

Answer 2

Berlin patient
 • Received a BM transplant (from a donor naturally resistant to HIV)
 • cART treatment halted
 • infection did not come back
 • has been off cART for 7 years

Mississippi baby
• very early treatment (within 30 hours of delivery)
• baby has been off cART for 2 years
• very low levels of virus, but no infection

Question 3

How do latent infected T cells arise?

What can they do?

Why is this a problem?

Answer 3

HIV infection of resting CD4+ T cells

At any point, the cell can re-activate and release virus
They can undergo homeostatic proliferation

HAART does not kill latently infected T cells

Question 4

Which cells does HAART target?

Answer 4

Activated CD4+ T cells

Does not target latently infected T cells

Question 5

What is the latent reservoir?

Answer 5

Many resting CD4+ T cells that are infected with HIV:

Predominantly:
• Central Memory T cells

Also:
• Thymic T cells
• Naïve T cells
• Effector T cells

HAART can not target these cells

Question 6

Describe anatomical reservoirs of HIV

List some

Answer 6

Certain parts of the body are sequestered from the drugs and the immune system
 • Brain
 • Lymph nodes
 • GIT
 • Testis

HAART can not target the infected cells in these organs

Question 7

What are the strategies for a HIV cure?

Answer 7

1. Activating latently infected cells
2. Make cells resistant to HIV
3. Eliminate residual virus replication
4. Enhance HIV-specific immunity

Question 8

Describe activating latent infection

Answer 8

1. Agent activates the integrated virus
2. Transcription, translation of HIV genes
3. HIV proteins expressed on the surface of the cell, virion shedding
4. Infected cell may die

Question 9

What are some agents of latent infection reactivation?

Answer 9

• HDACi (e.g. Vorinostat)
• Cytokines: IL-7
• Disulfiram

Question 10

Describe the function of HDACi

Answer 10

(Histone deacetylase inhibitors)

‘Turns genes on’; reactivates latently infected cells

1. HDACi deacetylates the histones of the HIV DNA
2. Expression of HIV genes

Cell may die

Question 11

What is observed in most patients when cART is stopped?

Answer 11

Rapid rebound of HIV RNA in serum

Question 12

List three barriers to cure of HIV infection

Answer 12

HIV persists despite HAART

1. Latently infected T cells
2. Residual viral replication
3. Anatomical reservoirs

Question 13

What is residual replication?

How often is it observed?

Answer 13

Observed in 1/3rd of people with HIV infection

cART is not effective at blocking replication of HIV in some T cells

Question 14

What is Vorinostat?

Describe its function

Answer 14

It is a Histone deacetylase inhibitor (HDACi)

Function:
• Acetylation of HIV genes integrated into host genome → genes turned ON
→ Activates latent HIV in vivo

Evidence:
Has been shown to greatly increase gag copies in patients (evidence of gene expression)

Question 15

What is a challenge to reactivation of latently infected cells?

Answer 15

Latently infected cells are rare

Question 16

Give an overview of some methods of making cells resistant to HIV

Answer 16

Gene therapy

1. Blockage of HIV protein action
   • RNA interference
2. Expression of an anti-viral factor
   • Mutant APOBEC 3G
3. Elimination of integrated HIV
   • LTR
4. Removal of an essential host factor
   • CCR5

Question 17

Describe how CCR5 can be used to make cells resistant to HIV infection

Is this safe?
What is the efficacy?

Answer 17

1. Isolation of CD4+ T cells from an HIV+ individual on cART
2. Nucleases cleave parts of DNA; removal of the gene for CCR5
3. Cells re-infused into the patient
4. HIV can not bind to the co-receptor, and thus cannot gain access to the host cell

Safety
• Infusion of CCR5 modified cells is safe

Efficacy:
• The CCR5 modified cells survive once re-infused

Question 18

How common are latently infected CD4+ T cells in patients receiving HAART?

Answer 18

60 per million CD4+ T cells

Thus, they are quite rare

This makes it difficult to get rid of the latently infected cells