Animal models
for AIDS disease
“Laboratory animal experiments
and animal models performing
in HIV/AIDS biomedical research”
Out line
1. Introduction & overview
2. Animal model content
3. Conclusion
1. Introduction
- Concept, purposes and overview of animal being used
in biomedical research
Animal
derive from
Anima
= living organism that can animated
Model = object of imitation
“Image of man”
Types of animal model
- Induced models
- Spontaneous models
- Negative models
- Orphan model
Today “animal models” are used in virtually
every field of research in both preclinical and
clinical studies
The aim of using animal models in biomedical
research is to reconcile biologic phenomena
between species or to reproduce delineated or
prominent characteristic
Animal experiments in scientific purposes
- To search for new knowledge
- To diagnose diseases
- To test new therapeutic technique and new medicines
- To detect and analyze drugs, hormones, and other
biological compounds
- To produce and test vaccines, sera, and other biological
compounds
- To test for toxicity, carcinogenicity, and teratogenecity
of new and old drugs and chemical compounds
Selection of animal models
It is virtually impossible to give specific rules for the
choice of the best animal model
Some general rules
-Appropriateness as an analog
-Transferability of information
-Genetic uniformity of organism -Background knowledge
-Cost and availability
-Ecological consequences
-Generalizability of the results
-Size of animal
-Numbers needed
-Life span
-Sex, age of animal
-Etc.
2.Animal models in AIDS
- Characteristic of AIDS animal models
- Classification of the models
- Non human primate models
- Murine models
- Feline models
- Large animal model
An Ideal AIDS animal model
- The test virus would be HIV itself
- The host would be small inexpensive,genetically and
immunologically well-characterized animal
- The target receptor would be CD4
- The tropism would be comparable with that observed in
human
- Disease development and mode of virus transmission
would resemble the situation observed in human
Classification of HIV/AIDS animal model
-Animal immunodeficiency retrovirus
Non human primate model
Ape
Genus Pan
Pan troglodyte (Chimpanzee)
Old world monkey
Genus Macaca, Papio, Cercocebus, etc
Diagram of primate evolution
Non human primate model
Study infection of lentivirus
HIV-1
HIV-2
SIV
Other non lentivirus model
MPMV
Study of HIV-1 in Chimpanzee
Pan troglodytes
- Chimpanzee can infected with HIV-1 but rarely develop
AIDS disease.
- No consistent changes in CD4+ cell.
- Vaccines study in chimpanzee are potential means of
evaluating the efficacy of candidate vaccines designed
to prevent human infection.
Study of HIV-2 in monkey
Pigtail macaque
(Macaca nemestrina)
Baboons
(Papio cynocephalus)
- This species are susceptible to infection with some
isolates of HIV-2.
- HIV-2 have been developed that induce AIDS-like
disease and depletion of CD4+ cell.
- Similarities in disease progression and development of
AIDS to human HIV infection.
Study of Simian immunodeficiency virus (SIV)
in non human primate model
-SIV is lentivirus and close related to HIV-1, HIV-2
-It share up to 50% similarity to HIV-1 in nucleotid level
and share about 88% of amino acid homology to HIV-2
HIV-1
SIVmac
Genome organization of primate lentivirus
Natural hosts of SIV are many African monkeys such as
African green monkey
(Cercopithecus aethiops)
Sooty mangabey
(Cercocebus atys)
Phylogenetic relationship of lentiviruses
- The heterologous host all develop disease that show
many parallels to human AIDS, the similarities
including
-CD4+ lymphoid cell and machrophage tropism
-CD4+ cell depletion
-Development of opportunistic infection and tumours
-Neurological manifestation
(Development of disease in macaque monkey is more rapid
than human)
-This model is facilitating studies of
viral genetics,
mechanism of pathogenesis,
drug interference, vaccination
and immunotherapy
Depending on the SIV strain used, on the dose and
route of inoculation and on the recipient host species
Non lentivirus primate model
Simian retrovirus type D (SRV-D)
-The prototype strain is the Mason-Pfizer monkey virus
(MPMV)
- Originally isolate from Rhesus macaque spontaneuos
breast tumour
-SRV-D is non lentivirus but belong to oncovirus subfamily
-Genomic organization of SRV-D is more simpler than
lentivirus
-Can induced simian AIDS (SAIDS) in SIV-negative
macaque monkey with short latency period (0.5- 3 years)
-SAIDS is characterize by wasting, chronic diarrhoea,
bacterial and viral infection, etc.
-The cell receptor for SRV-D is not CD4
(and not yet identified)
-The viral host range is broader.
-The SRV-D model is particularly helpful in studying
immunodeficiency induced by a widely occuring oncovirus
and model for the investigation of viral genomic determinant
and pathogenesis
Murine models
Mus musculus
-Lentivirus (HIV) models
Transgenic mice
SCID mice
-Non lentivirus model
Murine leukemia virus (MuLV)
Transgenic mice model
-Produce by introducing one or more viral genes into
the mouse germ line.
-Several transgenic line have been constructed to contain
either the full HIV-1 genome or various HIV-1 derived
gene
-eg. CD4C/HIV mice is constructed to express entire
HIV-1 genome in CD4 cell that serve as HIV-1 target
-This mice express the transgene at high level in the
thymus and moderate level in the spleen and lymph
node
-The transgene was not express in cells that were not
expected to express CD4.
-This mice exhibit other pathologies similar to those
demonstrated in HIV-1 infected individuals including
wasting, tubulo interstitial nephritis and lung lession
but did not appear to die of opportunistic infections.
-In contrast transgenic mice constructed without murine
CD4 enhancer remain healthy.
-Transgenic mice constructed to contain various HIV-1
gene demonstrate that nef is an important determinant in
eliciting the pathogenic process
-Transgenic mice can not yet model the process of infection
such as viral spread and the emergence of viral variants
-This approach may allow close examination of the disease
process occurring in tissues and may also useful in
exploring therapeutic strategies
SCID mice
SCID-hu model
hu-PBL-SCID model
SCID-hu model
-Rely on transplantation of human tissue in to SCID mice.
-Constructed by surgical implantation of human fetal
thymus and liver under the kidney capsules of SCID
mouse thus support the growth and differentiation of
human T and B lymphoid cells.
-Support infection with HIV-1 by IP or IV inoculation.
-Depletion of human CD4+ cells is observed.
-Most of the mice are clinically healthy .
-This model lacks of primary immune response.
-Unsuitable for the study of immune response to HIV and
pathogenesis in secondary lymphoid organ.
-Suitable for assessment of antiviral drug and gene
therapeutic strategies.
Hu-PBL-SCID models
-Constructed by transplantation of human peripheral blood
lymphocytes (PBL) or cord blood lymphocytes into the
peritoneal cavity of SCID mice.
-Can infected with HIV-1 .
-Cause depletion of human T cell.
-Most of the mice are clinically healthy.
-Limitation is inability to consistently elicit primary
immune responses.
-This model is useful for assessing viral pathogenic
properties, passive immune therapies, testing of anti-HIV
drugs and vaccines strategies.
Comparison of the two chimeric mouse model
Non lentivirus murine model
Murine acquire immunodeficiency syndrome (MAIDS)
-Induce by murine leukemia virus (MuLV).
-Mice infected with MuLV exhibit common clinical features
as human AIDS.
-Involving T,B lymphocyte dysfunction
-Enhance susceptibility to infection, etc.
-Murine AIDS is rapidly induce (8-12 weeks) and mice die
in 6 months.
-This model suitable for study of retrovirus-induced.
immunodeficiency disease , testing candidate antiviral agent
and study genetic resistant to retroviral immunodeficiency.
Feline model
Felis catus
Feline retrovirus
Lentivirus model
- Feline immunodeficiency virus (FIV)
Non lentivirus model
- Feline leukemia virus (FeLV-FAIDS)
FIV
-Cause by lentivirus (but not close related to HIV)
-FIV and HIV share basic structural features and .
commonalities of their life cycle.
-FIV infects CNS and results in predictable pathophysiology
similar to HIV-1.
-Suitable for study mechanisms by which lentiviruses
influence CNS function
-Useful model for human AIDS mechanisms of pathogenesis
(eg. neuropathogenesis)
and investigation of drug treatment, vaccination.
FeLV
-Cause AIDS-like disease in cats.
-Onset of clinical immunodeficiency prefigure by
replication of variant virus in bone marrow,other tissues.
-FeLV induce FAIDS is characterize by persistence FeLV
infection, lymphoid depletion, opportunistic infection,
diarrhoea, weight loss, etc.
-This model use to evaluate antiviral agent which act on
steps in the replication cycle which are conserve among
retroviruses (eg, protease , reverse trancriptase ) and can
be use to assess experimental single agent or combine
anti viral therapies for retrovirus infection and disease.
Pathogenesis of FAIDS
SIV do not develop disease in their natural host but can
cause disease in heterologous host such as many macaque
monkey
Rhesus macaque
(Macaca mulatta)
Cynomolgus monkey
(Macaca fasicularis)
Simian Immunodeficiency virus isolates
Large animal model
Equine infectious anemia virus (EIAV)
Visna-maedi virus (VMV)
Caprine arthritis-encephalitis virus (CAEV)
-Cause by lentivirus (not closely related to HIV).
-Not much practically use in research as the smaller animal.
-Use for study about pathogenesis of retrovirus infection
-The viruses are not T-lymphotropic and do not cause
immunodeficiency.
Clinical manifestation of lentivirus infection in natural hosts
3.Conclusion
- Advantages and disadvantages between different
species.
- Benefits and problems of using animal model
- Extrapolation
- Future prospects
Chimpanzee
-98.5% genetic resemble to human.
-Can infected with HIV-1.
-Good model for study cross reactive immune response.
-It rarely develop disease.
-It cant be use in sufficient numbers to provide statistically
significant results.
-Large size .
-Expensive.
-Not easy to handle.
Monkeys
-About 93% genetic similarity to human.
-Can provide enough numbers for study.
-Can be infected by many type of SIV,HIV2
-Results from different SIV strain can not be reliably
extrapolate to one another.
-Not easy to handle.
-Large size.
-expensive
-Hight risks of zoonosis.
Mice
-Small size,easy to handle inexpensive.
-High reproductive,short generation time and life span.
-Know about genetic makeup .
-Large number available in many strain.
-Can create desired system by genetic engineering.
-SCID mice does not have a standard human immune system.
-Incomplete and low number of repopulating human
lymphoid cells
-SCID mice does not develop AIDS like disease
Cats
-Not large size .
-Not difficult to handle .
-Not much expensive.
-Can be infected with FIV,FeLV and develop
immunodeficiency like syndrome.
-Cause nearly identical disease to HIV infection.
-Cat is far related genetic to human.
-FIV,FeLV are not closely related to HIV.
Benefits and problems of using animal model
Benefits
-Animal studies of toxicity, efficacy and pharmacokinetics
provide valuable scientific information toward identifying
potentially useful antiviral agents
-Helps approximate how drugs/vaccines might perform in
human.
-Helps to understand some certain mechanism of disease and
therapeutic agent observed in animal model.
-Study in animal is able to induced certain condition that can
not be done in human.
Problems
-Preclinical studies generally are inadequate to predic
whether an anti viral agent will be both effective and safe
when administered to human.(it is not until the agent enters
clinical trail in humans that is potential can be ascertained).
-There are large differences in the host cell enzymes
affinities for a specific antiviral compound among species.
-Difficulties between interspecies evaluation.
Extrapolation
Because there’re different between species and every
animal behave not same to human, to minimize
misinterprete of the results ,the extrapolation should meet
some general requirement.
-Taking a plurispecies approach.
-Metabolic patterns and speed must match between species.
-Confounding variables of metabolism must be controll.
-Experimental design and the life situation of the target
species must correspond.
Future prospects
Most model have their great potential in pathogenesis,immuneresponse analysis, vaccines and therapies study. Accordingly the
challenge for the future is to utilize the increasing knowledge of
molecular mechanism of HIV and HIV replication to elucidate all
aspects of the virus host relationships fully and thereby to
understand mechanism of pathogenesis in AIDS further.
Question like antibody enhancement of virus infection, induction
of auto immunity, presence of viral super antigens responsible for
T cell depletion and development of immune cell dysfunction and
tumours can should all be investigated in animal model in the near
future and there’re tendency to developments in the field of small
animal models for HIV disease.
Upcoming event
www.primate.wisc.edu/aids2000
Thanks for your attention.