SCID-hu mice: a model for studying disseminated HIV infection

Goldstein, Harris; Pettoello-Mantovani, Massimo; Katopodis, Nikos F.; Kim, Ana; Yurasov, Sergey; Kollmann, Tobias R.

doi:10.1006/smim.1996.0028

Cited by 20 publications

(7 citation statements)

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“…Liv/thy SCID hu mice have been used before to investigate novel compounds for their anti-HIV activity [5], [24]. However, detailed PK data were mostly lacking, thus making it difficult to interpret the antiviral potency of the compounds.…”

Section: Discussionmentioning

confidence: 99%

Humanized Mice Recapitulate Key Features of HIV-1 Infection: A Novel Concept Using Long-Acting Anti-Retroviral Drugs for Treating HIV-1

Nischang

Sutmuller²,

Gers-Huber

et al. 2012

PLoS ONE

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Background Humanized mice generate a lymphoid system of human origin subsequent to transplantation of human CD34+ cells and thus are highly susceptible to HIV infection. Here we examined the efficacy of antiretroviral treatment (ART) when added to food pellets, and of long-acting (LA) antiretroviral compounds, either as monotherapy or in combination. These studies shall be inspiring for establishing a gold standard of ART, which is easy to administer and well supported by the mice, and for subsequent studies such as latency. Furthermore, they should disclose whether viral breakthrough and emergence of resistance occurs similar as in HIV-infected patients when ART is insufficient. Methods/Principal Findings NOD/shi-scid/γ c null (NOG) mice were used in all experimentations. We first performed pharmacokinetic studies of the drugs used, either added to food pellets (AZT, TDF, 3TC, RTV) or in a LA formulation that permitted once weekly subcutaneous administration (TMC278: non-nucleoside reverse transcriptase inhibitor, TMC181: protease inhibitor). A combination of 3TC, TDF and TMC278-LA or 3TC, TDF, TMC278-LA and TMC181-LA suppressed the viral load to undetectable levels in 15/19 (79%) and 14/14 (100%) mice, respectively. In successfully treated mice, subsequent monotherapy with TMC278-LA resulted in viral breakthrough; in contrast, the two LA compounds together prevented viral breakthrough. Resistance mutations matched the mutations most commonly observed in HIV patients failing therapy. Importantly, viral rebound after interruption of ART, presence of HIV DNA in successfully treated mice and in vitro reactivation of early HIV transcripts point to an existing latent HIV reservoir. Conclusions/Significance This report is a unique description of multiple aspects of HIV infection in humanized mice that comprised efficacy testing of various treatment regimens, including LA compounds, resistance mutation analysis as well as viral rebound after treatment interruption. Humanized mice will be highly valuable for exploring the antiviral potency of new compounds or compounds targeting the latent HIV reservoir.

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Section: Discussionmentioning

confidence: 99%

Humanized Mice Recapitulate Key Features of HIV-1 Infection: A Novel Concept Using Long-Acting Anti-Retroviral Drugs for Treating HIV-1

Nischang

Sutmuller²,

Gers-Huber

et al. 2012

PLoS ONE

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“…Mice have been generated by transplantation technologies that maintain human adaptive immune system components including CD4 + T cells that support HIV-1 replication. 134 -136 SCID-hu mice (Severe Combined Immunodeficiency-humanized) 137,138 and BLT mice (Bone Marrow, Liver, Thymus) 139,140 are not necessarily optimal for transmission studies because they retain mouse mucosal and stromal components, and natural routes of HIV-1 transmission begin with mucosal exposure. Another interesting approach has seen the development of multi-layered stratified squamous epithelial membranes (MatTek, Boston, MA) that are derived in an ex vivo differentiation system, using human ectocervical epithelial cells 141,142 or vaginal epithelial cells.…”

Section: Model Systems Using Mixed Human Cell Populationsmentioning

confidence: 99%

Coming of age: reconstruction of heterosexual HIV-1 transmission in human ex vivo organ culture systems

et al. 2011

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“…Susceptibility to HIV‐1 infection has been mentioned as a cause of CD4 + CD8 + thymocyte depletion in the thymus,140 which has been exclusively associated with the presence of SI‐isolates 96. Phenotypically, double positive thymocytes disappear first, followed by the reduction of the matured CD4 + CD8 − thymocyte population.…”

Section: Overview Of the Hiv‐1 Infectionmentioning

confidence: 99%

“…In fact, the current understanding of HIV‐1 infection dynamics (as hepatitis‐C virus infection, among others) relies largely on the mathematical analysis of changes in plasma virus levels after perturbation of the chronically infected (quasi‐) steady‐state with potent antiviral treatment or plasma apheresis,33, 34, 95 due to the inability to infect animals with HIV‐1, and to observe the natural course of HIV‐1‐mediated disease 96. Moreover, the limited usefulness of an animal model for assessing the effectiveness of different treatments or the pathophysiology of HIV‐1 infection may be at least partially circumvented by mathematical modeling and current optimization techniques, which offer the possibility of quickly testing different realistic scenarios 28.…”

Section: Introductionmentioning

confidence: 99%