lecture 15 Flashcards
- numbers of new HIV infections globally are decreasing but 33 million currently infected - HIV is a retrovirus which can integrate in the host genome and persist indefinitely - HIV uses both CD4 and chemokine receptors (CCR5 and CXCR4) to enter a cell - natural mutations in CCR5 can protect from infection and have an effect on disease progression - CD4 loss is the hallmark of HIV infection but HIV causes multiple other immunological abnormalities including immune activation - cART has
1
Q
What reduces female acquisition?
A
- tenofovir containing microbicide reduces female acquisition by 40%
- BAT 24 coitally-related gel use
- insert 1 gel up to 12 Before sex
- insert 1 gel as soon as possible within 12 hours After sex
- no more than Two doses in 24 hours
(tenofovir is a nucleotide reverse transcriptase inhibitor)
- mimiced how we control reducing mother to child transmission
- if you give the mother drugs just before and just after delivery you can dramatically reduce transmission of virus from mother to baby (HIVNET 012 nevirapine regimen)
- this mimics the same approach but uses CAPRISA 004 tenofovir gel regimen
2
Q
What is PREP?
A
- pre-exposure prophylaxis
- give daily antivirals (tenofovir or truvada) either orally or vaginally
- highly effective in preventing transmission in monkey models
- oral truvada as PREP reduced risk of transmission amongst gay men by 40% (up to 70% if compliance is high)
3
Q
What is treatment as prevention?
A
- decreases in community viral load are accompanied by reductions in new HIV infections in SF
- heterosexual HIV-1 transmission after initiation of antiretroviral therapy: a prospective cohort analysis
- association of highly active antiretroviral therapy coverage, population
HPTN 052
- N=1763
- discordant couples in Africa, South America and US
- enrolled patients with CD4 counts 350-550
- randomised to either immediate HAART or defer until CD4< 0.001
- so significant majority were in people not on treatment
- ART reduces HIV transmission by 96% in HIV serodiscordant heterosexual couples
4
Q
Can universal cART end HIV?
A
- projections suggest that no intervention will lead to continued transmissions at a level similar to current
- ART CD4+ count <350 per µl will lead to a decrease but not particularly significant
- universal voluntary HIV testing and immediate ART could dramatically affect incidence
5
Q
What is the efficacy of HIV prevention?
A
- ART to prevent transmission most effective (96%)
- Male medical circumcision (70%)
- PREP (less effective according to studies in women than in gay men)
- vaginal microbicides showing efficacy
6
Q
What is the end of AIDS?
A
- seek, test and treat (still not done super well)
- prevention: vaccine, needed
- cure
7
Q
What do we mean by a cure for HIV?
A
Cure
- infectious diseases model
- elimination of all HIV-infected cells
- HIV RNA < 1 copy/ml
- sterilising cure
Remission
- cancer model
- long term health in absence of cART
- HIV RNA < 50 copies/mL
- functional cure
8
Q
Is HIV cure possible?
A
The Berlin Patient (7 years off ART)
- bone marrow transplant from a donor naturally resistant to HIV infection
The Mississippi baby (2 years of ART)
- very early treatment, 30 hours post delivery
- very, very low levels (functional cure)
Post treatment controllers
- ART in acute infection (VISCONTI; n=18; 8 years off)
- ART in chronic infection (Belgium; n=4; 6 months off)
9
Q
What are barriers to cure?
A
- latently infected T cells
- residual viral replication
- anatomical reservoirs
10
Q
What is HIV latency and infection of resting T-cells?
A
- predominantly infects activated CD4+ T cells –> replicates, leaves and kills the cell
- but patients on therapy –> virus can’t infect new cells
- resting CD4+ T cells: if the virus manages to enter it can integrate in the genome and not complete the virus life cycle
- two ways latently infected cells can be derived
- rarely an activated infected cell survives, reverts to become a central memory cell
- direct infection, assisted by tissue chemokines
latently infected cells are very long lived cells
- persist in people even when the viral load is undetectable/less than 50 copies/mL
- at any time this virus is fully infectious
- if it becomes activated, releases pathogen
- it someone on treatment, the virus can’t go anyway, so stays at very low levels
- latently infected cells can undergo homeostatic proliferation
- estimated about 60/million T cells are latently infected
- can be established in naive T cells, transitional memory and central memory T cells, rarely in the thymus
= latent reservoir
11
Q
What is residual replication?
A
- another way that HIV can persist
- residual viral replication
- few infected cells with ongoing rounds of replication
- ART blocks some of that
- evidence for residual replication in about one third of patients on cART
12
Q
What are anatomical reservoirs?
A
- virus can be sequestered into unique tissue compartments
- brain, lymphoid tissue, genitourinary tract and GIT
- in each of these there are latently infected cells, and other cells that can become infected e.g. DCs, macrophages, astrocytes
13
Q
What are strategies for cure?
A
- eliminate latently infected cells
- make cells “resistant” to HIV
- eliminate residual virus replication
- enhance HIV-specific immunity
14
Q
How can we eliminate late infection?
A
Activating latent infection
- if you activate the integrated virus you’ll start making RNA/viral proteins etc, virions when they exit
- this leads to cell death
- shock and kill
- things that activate latent infection = HADACi, Cytokines e.g. IL-7, disulfiram, quinolines, methylation inh, histone methyl transf inh, BET inh
- histone deacetylase inhibitors turn HIV genes “on”
- HDACi
- latently infected cells are rare but this affects all cells - big problem
15
Q
How can we make cells resistant to HIV?
A
- gene therapy
- block the action of an HIV protein
- RNA interference
- express an anti-viral factor
- mutant APOBEC 3G
- eliminate integrated HIV
- LTR
- remove an essential host protein
- CCR5
