Mice Transgenic for CD4-Specific Human CD4, CCR5 and Cyclin T1 Expression

A New Model for Investigating HIV-1 Transmission and Treatment Efficacy

Kieran Seay, Xiaohua Qi, Jian Hua Zheng, Cong Zhang, Ken Chen, Monica Dutta, Kathryn Deneroff, Christina Ochsenbauer, John C. Kappes, Dan R. Littman, Harris Goldstein

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Mice cannot be used to evaluate HIV-1 therapeutics and vaccines because they are not infectible by HIV-1 due to structural differences between several human and mouse proteins required for HIV-1 entry and replication including CD4, CCR5 and cyclin T1. We overcame this limitation by constructing mice with CD4 enhancer/promoter-regulated human CD4, CCR5 and cyclin T1 genes integrated as tightly linked transgenes (hCD4/R5/cT1 mice) promoting their efficient co-transmission and enabling the murine CD4-expressing cells to support HIV-1 entry and Tat-mediated LTR transcription. All of the hCD4/R5/cT1 mice developed disseminated infection of tissues that included the spleen, small intestine, lymph nodes and lungs after intravenous injection with an HIV-1 infectious molecular clone (HIV-IMC) expressing Renilla reniformis luciferase (LucR). Furthermore, localized infection of cervical-vaginal mucosal leukocytes developed after intravaginal inoculation of hCD4/R5/cT1 mice with the LucR-expressing HIV-IMC. hCD4/R5/cT1 mice reproducibly developed in vivo infection after inoculation with LucR-expressing HIV-IMC which could be bioluminescently quantified and visualized with a high sensitivity and specificity which enabled them to be used to evaluate the efficacy of HIV-1 therapeutics. Treatment with highly active anti-retroviral therapy or one dose of VRC01, a broadly neutralizing anti-HIV-1 antibody, almost completed inhibited acute systemic HIV-1 infection of the hCD4/R5/cT1 mice. hCD4/R5/cT1 mice could also be used to evaluate the capacity of therapies delivered by gene therapy to inhibit in vivo HIV infection. VRC01 secreted in vivo by primary B cells transduced with a VRC01-encoding lentivirus transplanted into hCD4/R5/cT1 mice markedly inhibited infection after intravenous challenge with LucR-expressing HIV-IMC. The reproducible infection of CD4/R5/cT1 mice with LucR-expressing HIV-IMC after intravenous or mucosal inoculation combined with the availability of LucR-expressing HIV-IMC expressing transmitted/founder and clade A/E and C Envs will provide researchers with a highly accessible pre-clinical in vivo HIV-1-infection model to study HIV-1 acquisition, treatment, and prevention.

Original languageEnglish (US)
Article numbere63537
JournalPLoS One
Volume8
Issue number5
DOIs
StatePublished - May 15 2013

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Cyclin T
cyclins
Human immunodeficiency virus 1
Luciferases
Transgenic Mice
HIV-1
genetically modified organisms
mice
luciferase
Renilla Luciferases
Clone Cells
clones
Gene therapy
infection
Transcription
HIV Infections
Infection
therapeutics
Vaccines
Genes

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Mice Transgenic for CD4-Specific Human CD4, CCR5 and Cyclin T1 Expression : A New Model for Investigating HIV-1 Transmission and Treatment Efficacy. / Seay, Kieran; Qi, Xiaohua; Zheng, Jian Hua; Zhang, Cong; Chen, Ken; Dutta, Monica; Deneroff, Kathryn; Ochsenbauer, Christina; Kappes, John C.; Littman, Dan R.; Goldstein, Harris.

In: PLoS One, Vol. 8, No. 5, e63537, 15.05.2013.

Research output: Contribution to journalArticle

Seay, Kieran ; Qi, Xiaohua ; Zheng, Jian Hua ; Zhang, Cong ; Chen, Ken ; Dutta, Monica ; Deneroff, Kathryn ; Ochsenbauer, Christina ; Kappes, John C. ; Littman, Dan R. ; Goldstein, Harris. / Mice Transgenic for CD4-Specific Human CD4, CCR5 and Cyclin T1 Expression : A New Model for Investigating HIV-1 Transmission and Treatment Efficacy. In: PLoS One. 2013 ; Vol. 8, No. 5.
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