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.
Objectives
1.
Definition of “cure”
2.
Elements of the reservoir
3.
Strategies toward a cure
4.
Overall challenges
The HIV infection pathway
Why aren’t ARV’s enough?- HIV
latency
Cell
Death
Resting State
History of HIV “cures”
•
Alternative (herbal therapies, dietary
supplements, visualization, etc.)
•
Cultural (rituals, practices, prayer, etc.)
Cure is NOT a
new idea
History of HIV “cures”
•
Time magazine wrote
that David Ho’s work
“might, just might, lead
to a cure”
What does cure mean-community
perspective
•
Living without treatment
•
Not transmitting virus to others
•
Complete viral eradication
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 not
Is “cure” the new “cancer”?
Concept
Eradication
Advantages
Powerful, galvanizing concept for
advocacy
Disadvantages
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
cure
Lifelong control?
Unfamiliar concept of cure
Remission
Appeals to concerns about
transmission
Not a ‘real’ cure if HIV present
More familiar to laypersons
When does remission start?
Less demanding, because no
guarantee of ‘lifelong’ control
Association with stigmatized
cancer
Denotes improvement but implies
need for vigilance, monitoring
Psychological uncertainty
Transmission?
S.Rennie
(2014)
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
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.
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 strokes
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
•
Early treatment is not in itself a cure
Natural immunity to HIV-1
Very rare
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.
• 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 CCR5Δ32 mutation.
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 Tcells for a minimum of 10 years without the
aid of antiretroviral therapy
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 debate
• Determining the location of latently infected cells
e.g. gut, T-cells
• Measuring the size of infected reservoirs
Current cure research strategies
1.
Kick and Kill
2.
Gene therapy/alteration
3.
Stem cell transplantation
4.
Therapeutic vaccines
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.
Kick and kill in action
“activate”
HIV US RNA
HIV proteins
HIV DNA
HIV DNA
HIV virions
Cell death
Kick and kill challenges
1.
Not every infected latent cell will become
active with latency reversing agents
2.
It has been shown that a latent cell may
need several rounds of stimulation to start
purging virus
3.
Finding effective latency reversing agents
that actually stimulate the cells inside the
body
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 HIV
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
Cell collection
Gene
editing
Patient
Cell
proliferation
Gene therapy/alteration challenges
1.
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.
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 system
Stem cell transplantation
•
Conditioning creates space for the donor
stem cells to replace the immune system.
• If the donor stem
cells lack the
CCR5 receptor,
HIV can almost
never enter the
cell
Basophil
CFU-B
Dendritic cell
CFU-DC
Macrophage
CMP
CFU-GM
CFU-M
Granulocyte
CFU-G
HSC
Platelets
HSC
CFU-MK
MPP
Erythrocyte
HSC
CFU-E
CLP
Early NK
NK cell
Pro-T
Pre-T
T-cell
Pro-B
Pre-B
B-cell
Stem cell transplantation challenges
1.
Currently this procedure is dangerous and
carries risks such as graft vs. host disease
2.
An extremely small percentage of the
population is naturally immune to HIV.
3.
Expensive and not scalable
Therapeutic vaccines
Strengthen 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.
Therapeutic vaccine challenges
•
HIV mutates very rapidly. It can be difficult to
find a broadly neutralizing antibody 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
General challenges to finding a cure
Participant Risk
Benefit
Global capacity
Knowledge
• 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
• need for greater understanding of HIV latency in both
infants and adult populations
Hope for the future
Treatment
Cure
Prevention
Prevention
Diagnosis
Treatment
Diagnosis
Collaborators