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