HIV Cure Research Training Curriculum HIV and Cure Basics Module by Jessica Handibode AVAC March The HIV CURE research training curriculum is a collaborative project aimed at making HIV cure research science accessible to the community and the HIV research field ID: 197119
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Slide1
The basics of HIV Cure Research
HIV
Cure Research Training Curriculum
HIV and Cure Basics Module by
:
Jessica
Handibode, AVAC
March
The HIV CURE
research training
curriculum is a collaborative project aimed at making HIV cure research science accessible to the community and the HIV research field. Slide2
Objectives
D
efinition of “cure”
Elements of the reservoir
Strategies toward a cure
Overall challengesSlide3
The HIV infection pathwaySlide4
Why aren’t ARV’s enough?- HIV latency
R
esting
S
tate
C
ell
D
eathSlide5
History of HIV “cures”
Alternative (herbal therapies, dietary supplements, visualization, etc.)
Cultural (rituals, practices, prayer, etc.)
Cure is
NOT
a new ideaSlide6
Time magazine wrote that David Ho’s work “might, just might, lead to a cure”
History of HIV “cures”Slide7
What does cure mean-community perspective
Living without treatment
Not transmitting virus to others
Complete viral eradication Slide8
What does cure mean-scientific perspective
Scientists are still unclear what it means to be “cured” of HIV
There is still debate over what biological signs indicate a potential cure
There is still debate over whether virus must be completely gone from the body or notSlide9
Is “cure” the new “cancer”?
Concept
Advantages
Disadvantages
Eradication
Powerful, galvanizing concept for advocacy
Ambiguity
between population and clinical senses
Too high a bar?
Sterilizing
cure
Seductive idea of definitive absence of HIV
No reliable test to confirm viral absence Functional cure
Less demanding than sterilizing cureAppeals to concerns about transmissionLifelong control?
Unfamiliar concept of cure
Not a ‘real’ cure if HIV present Remission More familiar to laypersonsLess demanding, because no guarantee of ‘lifelong’ control
Denotes improvement but implies need for vigilance, monitoring When does remission start?
Association with stigmatized cancerPsychological uncertaintyTransmission?
S.RennieSlide10
What is a reservoir?
The collection of HIV infected resting cells
Potential reservoirs include T-cells, macrophages and tissue compartments like gut and brain that contain these cells.
Nature Reviews Immunology 14, 24-35
Nature Reviews Immunology
14
,
24–35
(2014)Slide11
How is a reservoir maintained?
Most HIV reservoir maintenance pathways are unknown.
This is a topic of intense research in the scientific community.
Active reservoirs
are cells that produce virus in the presence of Antiretroviral Therapy. Generally these reservoirs are found in the tissue. Slide12
Does size matter?
Different assays can
measure
the size of the reservoir. There are several ways to do this including measuring HIV RNA or DNA
The size of an individual’s reservoir can vary greatly. Individuals diagnosed later in infection tend to have larger
reservoirs
A larger reservoir
means
greater and more persistent immune activation
Sustained immune activation can lead to chronic inflammation, among other side effects which can lead to dangerous conditions like heart attacks and strokesSlide13
Early treatment and cure
Treating HIV early may reduces the size of the reservoir & it may also prevent reservoirs from forming in certain parts of the body
The definition of “early” is currently being debated in the scientific community
E
arly treatment is
not
in itself a cureSlide14
Natural immunity to HIV-1
No CCR5 Receptor
Homozygous
There is a very small percentage of the population who are naturally resistant to HIV. These individuals
are
of Northern European origin.
Very rare
In order to have a T-cell without a CCR5 receptor you must have two genes (one from each parent) with
the CCR5
deleted
segments.
A person with
two deleted CCR5 gene segments is
homozygous for the CCR5
Δ
32 mutation
. Slide15
Living with HIV without treatment
Elite Controller:
someone who can keep nearly undetectable levels of virus without antiretroviral therapy
Long Term Non-
Progressor
:
someone
who maintains a normal count of CD4 and CD8 T-cells for a minimum of 10 years without the aid of antiretroviral therapySlide16
Scientific challenges to finding a cure
Understanding the latency pathway of HIV
Why do cells remain latent?
How does the reservoir persist over a lifetime
What, if any, effect
does sex
have on latency?
Factors
still unknown/under
debateDetermining the location of latently infected cells e.g. gut,
T-cellsMeasuring the size of infected reservoirsSlide17
Current cure research strategies
Kick and Kill
Gene therapy/alteration
Stem cell transplantation
Therapeutic vaccinesSlide18
Kick and Kill
This strategy aims at forcing cells out of a resting state so virus can be released and killed
Once cells begin to replicate, again they can be identified and killed
The virus that is released into the blood stream can infect cells, however effective ART blocks replication
However a kill component, like a therapeutic vaccine will be needed to eliminate virus.Slide19
Kick and kill
in action
HIV DNA
HIV US RNA
HIV DNA
HIV proteins
HIV
virions
“activate”
Cell deathSlide20
Kick and kill challenges
Not every infected latent cell will become active with latency reversing agents
It has been shown that a latent cell may need several rounds of stimulation to start purging virus
Finding effective latency reversing agents that actually stimulate the cells inside the bodySlide21
Gene therapy/alteration
The aim is to remove a key element the virus needs to invade the cell
The CCR5 receptor is one of the necessary binding sites for HIV to enter a cell
Knocking out the genes that cause the CCR5 receptor will make cells resistant to HIVSlide22
Gene therapy/alteration
Scientists are working on ways to modify, culture and reintroduce these cells into the body of patients to increase resistance to HIV
Patient
Cell proliferation
Cell collection
Gene editingSlide23
Gene therapy/alteration challenges
Gene therapy does not kill existing virus. It just alters cells, making them HIV resistant or possibly improving immune fighting capabilities
2. Editing genes can lead to “off targets” or alterations in genetic sequences that was unintended. This could lead to side effects that include cancer. Slide24
Stem cell transplantation
The goal is to use stem cells to produce new HIV-resistant cells in the body
When undergoing a stem cell transplant a person must undergo a dangerous conditioning process to wipe out their entire immune system
The conditioning process can involve several different types of drugs as well as radiation
to completely kill the immune systemSlide25
Stem cell transplantation
Conditioning creates space for the donor stem cells to replace the immune system.
Macrophage
Dendritic cell
T-cell
Erythrocyte
B-cell
HSC
HSC
HSC
MPP
CLP
CMP
Granulocyte
Basophil
Platelets
Pro-T
Pro-B
Pre-T
Pre-B
Early NK
NK cell
CFU-GM
CFU-B
CFU-DC
CFU-M
CFU-G
CFU-MK
CFU-E
If the donor stem cells
lack
the CCR5
receptor,
HIV can almost never enter the cellSlide26
Stem cell transplantation challenges
Currently this procedure is dangerous and carries risks such as graft vs. host
disease
An extremely small percentage of the population is naturally immune to HIV.
Expensive and not scalableSlide27
Therapeutic vaccines
S
trengthen the immune responses, to enable the destruction of newly infected cells in order to achieve a functional cure
Broadly neutralizing antibodies, antibodies that can bind and kill a variety of HIV mutations, are being pursued in both preventative and curative strategies.Slide28
Therapeutic vaccine challenges
HIV mutates very rapidly. It can be difficult to find a
that can effectively work long enough to knock out HIV
Over stimulation of the immune system can lead to an increase of target cells for the virus
broadly neutralizing
antibodySlide29
General challenges to finding a cure
Participant Risk Benefit
Global capacity
unlike treatment, most people living with HIV have effective regimens that work with their daily routine. Not all cure strategies will be worth the risk to study participants
there are very few labs in the world that have the technical equipment and personnel capabilities to conduct cure research
Knowledge
need for greater understanding of HIV latency in both infants and adult populationsSlide30
Hope for the futureSlide31
Collaborators