Lecture 15 - HIV Biomedical Prevention, Possible Cures Flashcards
Behavioural ways to prevent HIV
1)
2)
3)
1) Education
2) Testing
3) Condoms
Biological ways to prevent HIV 1) 2) 3) 4)
1) Vaccine
2) Microbicides
3) Antiretroviral therapy
4) Treat sexually-transmitted infections (increase risk of transmission)
PREP
Pre-exposure phrophylaxis
Treat with cART before exposure to HIV
Possible vaccine approaches 1) 2) 3) 4) 5) 6) 7)
1) Recombinant proteins
2) DNA vaccines
3) Live vector vaccines
4) Live attenuated
5) Prime boost
6) Broadly-neutralising antibodies
7) CMV vectors
HIV recombinant protein vaccine
Good antibody response, no T cell response
Provides no protection
HIV DNA vaccines
Good T cell response, poor antibody response
HIV live-vector vaccines
1) Non-replicating poxvirus vector provides good T cell activation
2) Ad5 vector used in STEP trial. Might have increased risk of disease
Problems with live attenuated HIV vaccine
Potentially unsafe
Could revert to virulence
What is a prime boost vaccine?
DNA vaccine + protein or vector
Possible pro of CMV vaccine
Constant antigen presentation
Example of a prime boost vaccine
ALVAC + gp120
Provided 30% protection
Example of a DNA prime + recombinant Ad5 boost vaccine
1) DNA vaccine for gag, env, nef, pol at weeks 0, 4, 8
2) rAd5 boost of gag, pol, env at week 24
Not effective
When do broadly neutralising antibodies normally appear?
1-2 years into infection
At this point in infection, don’t help patient
Leukophoresis
Isolates T cells
Immune response elicited by CMV vectors
1)
2)
3)
1) Unconventional MHCII-restricted CD8+ response
2) Breadth of epitope recognition
3) Promiscuity
How much does male circumcision protect against HIV infection?
70%
How does male circumcision decrease HIV infection rate?
Langerhans cells in foreskin are absent
Langerhans cells are what bring HIV into lymph nodes
Microbicide that can protect against HIV infection
Tenofovir
Tenofovir
Nucleoside reverse transcriptase inhibitor
BAT24 gel
Contains tenofovir
Applied 24 hours before sex, 24 hours after sex
Efficacy of tenofovir
30% reduction in female transmission
Antivirals given as PREP
Tenofovir
Truvada
PREP
Give tenofovir, truvada daily to uninfected, but at risk of infection
PREP efficacy
Oral truvada decreased transmission among gay men by 40%, up to 70% if compliance was high
Does treatment with HAART decrease chance of transmission?
Yes
97% reduction in discordant couples
Discordant couple
One partner HIV+, one partner HIV-
Most effective means of preventing transmission
ART treatment
Two different models of HIV cure
1) Cure - Complete absence of HIV-infected cells
2) Remission - Undetectable level of HIV with cessation of ART
Sterilising HIV cure
A complete cure
<1 HIV RNA copy/mL
Functional HIV cure
Remission of HIV
<50 HIV RNA copy/mL
Proof of possibility of cure
1)
2)
1) Berlin patient - Cured after receiving bone marrow transplant from a naturally-resistant donor
2) Mississippi baby - Born to HIV+ mother, given ART within 30 hours of birth. Cleared infection
Reasons for viral resurgence after ART stopped
1)
2)
3)
1) Latently-infected T cells
2) Residual viral replication
3) Anatomical reservoirs
HIV latency
In resting T cells, HIV proteins not expressed
When T cell is activated, HIV replication begins, other cells infected
Latent cells are very long-lived (EG: macrophages, memory T cells) and always infectious
Estimated number of latently-infected T cells in a patient controlling HIV with ART
~60/million T cells infected
Latent reservoir of cells
Naive, transitional memory, central memory T cells
Residual replication
ART can’t prevent all HIV replication
Replication continues at a low level
Anatomical reservoirs
Brain, testes, gut, lymph nodes
Cells in anatomical reservoirs in which HIV resides
Macrophages
Astrocytes
Dendritic cells
Possible way to eliminate infected cells
1)
2)
1) Activate latently-infected cells
2) This makes cells display virus-infection markers, will be destroyed by immune system
Candidate for activating latently-infected cells
Histone deacetylase inhibitors
Promote transcription of all genes, including HIV genes –> Turn HIV genes on
Possible anti-HIV gene therapies 1) 2) 3) 4)
1) RNA interference –> block action of HIV genome
2) Express an anti-viral factor –> Mutant APOBEC3G
3) Remove an essential host factor –> CCR5
4) Block LTR of integrated HIV
Way to eliminate CCR5 expression
Zinc-finger nuclease heterodimer
Cuts part of CCR5, inactivates it
Possible application of gene therapy 1) 2) 3) 4)
1) Take blood, isolate T cells with leukophoresis
2) Remove CCR5 from T cells with zinc-finger nucelase
3) Reinfuse T cells
4) HIV will kill off CCR5+ cells, not CCR5- cells
