Download Animal models HIV Cure Research Training Curriculum

ANIMAL MODELS
HIV Cure Research Training Curriculum
The HIV CURE training curriculum is a collaborative project aimed at making HIV
cure research science accessible to the community and the HIV research field.
Session Goals
•
Understand purpose of animal models in
HIV cure research
•
Identify two major types of animal models
• As well as their benefits and disadvantages
•
Know mechanisms to be tested in animal
models for cure research
Why we use animal models
•
Researchers can investigate disease models thoroughly
to assess risks and benefit
•
Models can be evaluated using methods that may not be
possible in humans
•
Work in animals may impose a level of harm that would
be unethical in humans
•
Offer reliable and reproducible experimental systems for
research
•
Able to control timing, dose and route of infection
What is an animal model?
•
Living but non-human
•
Has features similar to the system being
studied or has a feature that is
advantageous for research
•
Have become an essential component of
translational research for HIV/AIDS
• No two humans are alike, so model should address a
specific problem to be evaluated
Timeline to drug development
Preclinical research
Lab research for
proof of concept
Clinical testing
Roll out
Animal model
Phase
1
Phase
1I
Phase
III
NDP filing
Accepted
and
approved
application
Product
launch.
Post market
surveillance.
Animal models in HIV
•
Average rate of successful transition from
animal models to clinical research is low
•
Two major categories of animal models used
in HIV research are:
1. Humanized mice
2. Non-human primates
Humanized mice: overview
Isolate human hematopoietic stem cells (HSC)
a. Blood cells that give rise to other blood cells
b. Located in bone marrow
Humanized mice: overview
Engraft immunodeficient mouse with human
HSC to develop humanized mouse
•
Mouse model that shares similar features with
human immune system
Immunodeficient
mouse
Humanized mouse
Humanized mice: overview
•
Alternatively, can also have
immunocompetent mice expressing human
genes by transgenesis
•
Advantages of engraftment model is that
the lympocytes developed in mice from
hHSCs undergo selection and are then
tolerant to the mouse host
Humanized mice: benefits
•
Relatively inexpensive & simple
• Cheaper to acquire than other models
•
Small size
• Lower maintenance costs
• Lower requirements for storage/space
•
Able to genetically mutate because it is a small
model
•
Can generate multiple cohorts of mice from
multiple human donors
Humanized mice: challenges
•
Unlike other small animal models, can not
breed humanized mice
•
Can’t create large cohorts from a single
human donor
•
Lack normal lymphoid structure and
function
Non-human primates: overview
•
Physiologically and immunologically similar to
humans
• Provides advantage over other models
•
There are many models based on the macaque
species
• Rhesus, pigtail, cynomolgus, etc.
•
SIV is not pathogenic in it’s host but NHP
models are available with particular challenge
viruses that allow for pathogenic SIV infection
of macaque
Non-human primates: benefits
•
The infection pathway of SIV is closely
related to HIV in humans
•
Non-human primates share physiological
similarities with humans. Such as:
• Gastrointestinal tracts – important in evaluating
reservoir
• Reproductive system
Non-human primates: challenges
•
Very costly to develop and maintain long term
•
Natural resistance to non-nucleoside reverse transcriptase inhibitors
•
Genetic variation between animals
• Can make work difficult in terms of controlling for variables
• MHC expression can vary
•
Can’t infect with HIV but alternatives produce many important, key
elements of HIV infection
• Can infect with SIV or SHIV
• Not identical to HIV but very close in function
•
NHP models used for HIV cure research are underdeveloped compared
with those used in HIV transmission studies
•
Use of NHPs banned in some countries due to ethical concerns
Animal models and cure research
•
No consensus on how animal models should be used for cure research
•
But in animal models, can monitor HIV replication
• Monitor viral load levels
• CD4+ T cell depletion
• Immune activation
•
Also, thorough characterization of persistent reservoirs (active and
persistent)
• Using consistent and invasive sampling of reservoirs
•
Assess effects of therapeutic interventions
• Particularly advantageous for ATI
•
Models can also be used to assess the source of viral rebound after
treatment interruption
Animal models and cure research
Animal models can be particularly useful in
evaluating HIV cure mechanisms in the
following areas:
• Viral expression activators
• Immune cell exhaustion
• Can be challenged with HIV multiple times
• Measure/quantify the response
• Measuring the HIV reservoir - in the brain
especially
Conclusions
•
Animal models have contributed greatly to HIV
research generally
•
Models are being optimized for use in HIV cure
research
• Many useful applications and avenues to explore in viral
eradication
•
Animal models provide many benefits but also
pose challenges
• Even within a category of animal model, each sub-type is
characterized by it’s own unique set of challenges