Lecture 24: HIV (3) Flashcards
What are the differences between cure and remission?
What is the model for each?
What is the likelihood of both?
Cure: ‘infectious disease model’
* eradication of all HIV-infected cells
* ‘sterilising cure’
* likely to be very difficult in HIV
2. Remission: ‘cancer model’ - its the pathway to a HIV cure
* long term health in the absence of cART
* HIV still present at low levels
* ‘functional cure’
* rare, but not impossible
What are the major barriers to a cure for HIV?
- Latently infected T cells
Residual viral replication
Anatomical reservoirs
What are the new concepts in HIV persistence and latency?
- Reservoir activity
- Proliferation
- Position matters
- Defective and intact virus
- Evade immunity
- Primed to survive
What single cell technologies are transforming our understanding of HIV latency?
- Phenotypic and pro-viral sequencing (PheP-Seq)
- Focused interrogation of cells by nucleic acid detection and sequencing (FIND-seq)
What is the importance of HIV integration sites?
- Integration sites determine the likelihood of a virus being active or silent
- New techniques determine the integration site, sequence, and transcription in the same cell
- In a subset of people, intact virus is only found in gene deserts meaning limited or no HIV transcription
What is the latent reservoir?
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
Describe anatomical reservoirs of HIV
List some
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
What are the strategies for a HIV cure?
Activating latently infected cells
Make cells resistant to HIV
Eliminate residual virus replication
Enhance HIV-specific immunity
What are some agents of latent infection reactivation?
HDACi (e.g. Vorinostat)
Cytokines: IL-7
Disulfiram
Describe the function of HDACi
(Histone deacetylase inhibitors)
‘Turns genes on’; reactivates latently infected cells
HDACi deacetylates the histones of the HIV DNA
Expression of HIV genes
Cell may die
What is observed in most patients when cART is stopped?
Rapid rebound of HIV RNA in serum
What is residual replication?
How often is it observed?
Observed in 1/3rd of people with HIV infection
cART is not effective at blocking replication of HIV in some T cells
What is Vorinostat?
Describe its function
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)
What are some strategies to target HIV?
- Very early ART
- Latency reversal
- Pro-apoptotic drugs
- Immunotoxins
- Latency silencing
- Gene editing
What are some strategies to target the immune system?
- Broadly neutralising antibodies (bNAbs)
- T-cell vaccines
- Immunomodulation
- CAR T-cells