High-throughput humanized mouse models for evaluation of HIV-1 therapeutics and pathogenesis

Tynisha Thomas, Kieran Seay, Jian Hua Zheng, Cong Zhang, Christina Ochsenbauer, John C. Kappes, Harris Goldstein

Research output: Chapter in Book/Report/Conference proceedingChapter

5 Citations (Scopus)

Abstract

Mice cannot be used as a model to evaluate HIV-1 therapeutics because they do not become infected by HIV-1 due to structural differences between several human and mouse proteins required for HIV-1 replication. This has limited their use for in vivo assessment of anti-HIV-1 therapeutics and the mechanism by which cofactors, such as illicit drug use accelerate HIV-1 replication and disease course in substance abusers. Here, we describe the development and application of two in vivo humanized mouse models that are highly sensitive and useful models for the in vivo evaluation of candidate anti-HIV therapeutics. The first model, hu-spl-PBMC-NSG mice, uses NOD-SCID IL2rγ-/- (NSG) mice intrasplenically injected with human peripheral blood mononuclear cells (PBMC) which develop productive splenic HIV-1 infection after intra-splenic inoculation with a replication-competent HIV-1 expressing Renilla reniformis luciferase (HIV-LucR) and enables investigators to use bioluminescence to visualize and quantitate the temporal effects of therapeutics on HIV-1 infection. The second model, hCD4/R5/cT1 mice, consists of transgenic mice carrying human CD4, CCR5 and cyclin T1 genes, which enables murine CD4-expressing cells to support HIV-1 entry, Tat-mediated LTR transcription and consequently develop productive infection. The hCD4/ R5/cT1 mice develop disseminated infection of tissues including the spleen, small intestine, lymph nodes and lungs after intravenous injection with HIV-1-LucR. Because these mice can be infected with HIV-LucR expressing transmitted/founder and clade A/E and C Envs, these mouse models can also be used to evaluate the in vivo efficacy of broadly neutralizing antibodies and antibodies induced by candidate HIV-1 vaccines. Furthermore, because hCD4/R5/cT1 mice can be infected by vaginal inoculation with replication-competent HIV-1 expressing NanoLuc (HIV-nLucR)-, this mouse model can be used to evaluate the mechanisms by which substance abuse and other factors enhance mucosal transmission of HIV-1.

Original languageEnglish (US)
Title of host publicationMethods in Molecular Biology
PublisherHumana Press Inc.
Pages221-235
Number of pages15
Volume1354
DOIs
StatePublished - 2016

Publication series

NameMethods in Molecular Biology
Volume1354
ISSN (Print)10643745

Fingerprint

HIV-1
Therapeutics
HIV
HIV Infections
Blood Cells
Cyclin T
Renilla Luciferases
AIDS Vaccines
Inbred NOD Mouse
Street Drugs
Therapeutic Uses
Infection
Neutralizing Antibodies
Intravenous Injections
Transgenic Mice
Small Intestine
Substance-Related Disorders
Spleen
Lymph Nodes
Research Personnel

Keywords

  • Antiretroviral treatment
  • HIV-1
  • Mouse model

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics

Cite this

Thomas, T., Seay, K., Zheng, J. H., Zhang, C., Ochsenbauer, C., Kappes, J. C., & Goldstein, H. (2016). High-throughput humanized mouse models for evaluation of HIV-1 therapeutics and pathogenesis. In Methods in Molecular Biology (Vol. 1354, pp. 221-235). (Methods in Molecular Biology; Vol. 1354). Humana Press Inc.. https://doi.org/10.1007/978-1-4939-3046-3_15

High-throughput humanized mouse models for evaluation of HIV-1 therapeutics and pathogenesis. / Thomas, Tynisha; Seay, Kieran; Zheng, Jian Hua; Zhang, Cong; Ochsenbauer, Christina; Kappes, John C.; Goldstein, Harris.

Methods in Molecular Biology. Vol. 1354 Humana Press Inc., 2016. p. 221-235 (Methods in Molecular Biology; Vol. 1354).

Research output: Chapter in Book/Report/Conference proceedingChapter

Thomas, T, Seay, K, Zheng, JH, Zhang, C, Ochsenbauer, C, Kappes, JC & Goldstein, H 2016, High-throughput humanized mouse models for evaluation of HIV-1 therapeutics and pathogenesis. in Methods in Molecular Biology. vol. 1354, Methods in Molecular Biology, vol. 1354, Humana Press Inc., pp. 221-235. https://doi.org/10.1007/978-1-4939-3046-3_15
Thomas T, Seay K, Zheng JH, Zhang C, Ochsenbauer C, Kappes JC et al. High-throughput humanized mouse models for evaluation of HIV-1 therapeutics and pathogenesis. In Methods in Molecular Biology. Vol. 1354. Humana Press Inc. 2016. p. 221-235. (Methods in Molecular Biology). https://doi.org/10.1007/978-1-4939-3046-3_15
Thomas, Tynisha ; Seay, Kieran ; Zheng, Jian Hua ; Zhang, Cong ; Ochsenbauer, Christina ; Kappes, John C. ; Goldstein, Harris. / High-throughput humanized mouse models for evaluation of HIV-1 therapeutics and pathogenesis. Methods in Molecular Biology. Vol. 1354 Humana Press Inc., 2016. pp. 221-235 (Methods in Molecular Biology).
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