Table 1.

List of animal models used in NeuroHIV research.

Model	Mutation/changes	Expression / Target organ	Phenotype	Applications	Advantages	Limitations	Drug abuse
iTat mice [50, 130, 131, 360].	Tat protein expressed in the brain astrocytes under inducible promoter.	Brain–astrocytes.	Increased astrocytosis, loss of neuronal dendrites, and neuroinflammation.	To study the effects of Tat on astrocytes including the astrocyte-mediated Tat neurotoxicity, Tat-impaired neurogenesis, Tat-induced loss of neuronal integrity, and exosome-associated Tat release and uptake.	Depletion of T cells is not necessary to create these models.	Expressed only in brain astrocytes, Expression of tat protein is driven by doxycycline, which has neuroprotective property [131, 360]. Doxycycline inducible promoter is leaky, so small amounts of Tat protein is expressed in early stages of development, because of this leakiness an immune response did not seen after tat induction [158].	Methamphetamine [140], cocaine [141, 361, 362], Morphine [142–144]
EcoHIV mice [61, 151]	The coding region of gp120 in HIV virus was replaced with mouse leukemia virus gp80 to infect mice.	Immune Cells, Spleen, and Brain.	EcoHIV-infected animals showed more macrophages and monocytes.	In the absence of T cells, HIV-infected macrophages are sufficient for induction of cognitive impairment in mice. Good experimental model for NeuroAIDS Therapy.	EcoHIV is a good model to study some of the neuron type-specific neurotoxic functions of HIV. EcoHIV constitutively expressed in mice for up to 16 months.	EcoHIV enters cells through CAT-1 receptor [61].	Methamphetamine [160], Morphine [154].
gp120 transgenic mice [167]	A transgenic gp120 mice model was generated by inserting the portion of the HIV env gene that encodes gp120 into the mouse genome under the control of a glial fibrillary acidic protein (GFAP) promoter, resulting in gp120 protein expression by brain astrocytes.	Brain-astrocytes.	Abnormal dendrite morphology, decreased synaptic and dendritic density, Increased astrocytosis.	Good animal model for neuroAIDS research	Non-infectious model, Neurodegene ration and glial cell activation mimics that of HIV encephalitis. Protein express only in brain astrocytes.	Viral protein is present throughout the lifespan might promote survival of abnormally robust neuronal populations [158].	Methamphetamine [174–176], Morphine: [138, 172].
SCID [191, 363-366]	Mutation in the gene for protein kinase, DNA activated, catalytic polypeptide (PRKDC).	Thymus, spleen, lymph node.	Absence of functional B cells and T cells.	To study the human immune system and human disease in a small animal model.	Useful tool for Immunology, Inflammation and Autoimmunity Research, Xenograft/transplant host AIDS research tool.	In certain circumstances like unsterile conditions, can lead to activation of NK cells, leakiness of SCID mice.[195, 196]	Morphine [191], Methamphetamine [192, 193], cocaine: [194, 367].
Tg 26 Mice [103, 108]	Loss of neuronal dendrites, loss of synapses. Kidney disease, HIV-associated nephropathy. Tg26 mice exhibit proteinuria.	Ubiquitous	Loss of neuronal dendrites, loss of synapses. Kidney disease, HIV- associated nephropathy. Tg26 mice exhibit proteinuria.	Animal model for human HIV-associated nephropathy (HIVAN).	HIV-1-Tg26 mouse model has been used extensively to study the pathogenesis of HIVAN because these mice develop renal disease mimicking human HIV associated Nephropathy.	Approximately 15% of Tg 26 mice spontaneously develop leukemia/lymphoma [368].	Cocaine [116], Morphine [117], Methamphetamine [173, 369].
HIV transgenic rats [56, 220, 370]	Plasmid containing non-infectious HIV provirus and host cell flanking regions were microinjected into fertilized rat eggs.	lymph nodes, thymus, liver, kidney, and spleen.	Cataracts, Kidney and heart damage and loss of lymphocytes.	Good model for neuroHIV study.	Transgenic rat is a noninfectious small-animal model of HIV-1 pathogenesis because it efficiently express viral gene in lymph nodes, spleen, thymus, and blood. Useful to study the mechanisms underlyin HIV - associated disease progression caused by HIV proteins.	This model is not useful to study the initial infection stage of HIV and there is no viral replication in the HIV-1Tg rat [228].	Methamphetami ne[224, 371, 372], Morphine, [225, 226], Cocaine: [227].
SIV and SHIV monkey models [235–238, 309]	Intravenous inoculation of SIV virus.	Brain, Heart, and Kidney.	Reduced number of CD4+ T cells.	Good model system for HIV pathogenesis and vaccine research.	SIV is genetically, antigenically and morphologically close to HIV. SIV infected monkeys are immunosuppressed and display neuropathological and behavioral features are identical to HIV-infected humans.	higher maintenance costs, Not susceptible to HIV-1 [240].	Morphine [239, 315, 316], Cocaine [324], Methamphetami ne[325–327].
FIV model [328]	FIV is a natural lentiviral. The integrated provirus possesses gag, pol, and env genes, common elements of all retroviruses.	Liver, Kidney, Brain and Lung.	Progressive CD4+ T cell depletion, a deficit in the humoral immune response, and the dysregulation of cytokine expression.	Valuable animal model for the development of antiretroviral drugs.	Not large in size and not difficult to handle, The models can be infected with FIV, FeLV and develop immuno deficiency-like syndrome.	Cat’s genetic makeup is far related to human FIV, FeLV are not closely related to HIV [330, 357].	Methamphetami ne[354, 355], Morphine[352, 353],
scid-hu-Thy/Liv mice. [373, 374]	SCID mice are implanted with human liver and thymus.	Thymus and Liver	Decrease in the CD4/CD8 ratio	This model is useful to study HIV pathogenesis and to test the efficacy of antiretroviral drugs for HIV replication.	These mice have human liver and thymus cells, which are the target organ for antiretroviral drug uptake and action.	Substantial degree of ‘leakiness’ in certain mouse strains (leading to the development of mouse T cells and B cells in older animals. This model cannot be used to study mucosal transmission of HIV-1 [240].	N/A
Humanized microglial mice. [216, 375, 376]	Mice express a humanized form of the microglial growth factor CSF1, which is essential for microglial maintenance, and lack of two immune factors required for rejection of foreign cells.	Brain	N/A	This model will be useful to investigate how human and mouse microglia function differently in normal and HIV conditions. Useful to study the role of human microglia in brain development and degeneration.	Useful to study the pathophysiology of the human cells within an intact brain.	Many human cytokines and other factors are species specific [216, 376] .	N/A