Transcript Animal models25

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