Mice transgenic for CD4-specific human CD4, CCR5 and cyclin T1 expression: a new model for investigating HIV-1 transmission and treatment efficacy.
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...
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2013
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oai:doaj.org-article:81ace1bf4b8b412ab2052854cde06e082021-11-18T07:45:40ZMice transgenic for CD4-specific human CD4, CCR5 and cyclin T1 expression: a new model for investigating HIV-1 transmission and treatment efficacy.1932-620310.1371/journal.pone.0063537https://doaj.org/article/81ace1bf4b8b412ab2052854cde06e082013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23691059/?tool=EBIhttps://doaj.org/toc/1932-6203Mice 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.Kieran SeayXiaohua QiJian Hua ZhengCong ZhangKen ChenMonica DuttaKathryn DeneroffChristina OchsenbauerJohn C KappesDan R LittmanHarris GoldsteinPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 5, p e63537 (2013) |
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| topic |
Medicine R Science Q |
| spellingShingle |
Medicine R Science Q 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 Mice transgenic for CD4-specific human CD4, CCR5 and cyclin T1 expression: a new model for investigating HIV-1 transmission and treatment efficacy. |
| description |
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. |
| format |
article |
| author |
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 |
| author_facet |
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 |
| author_sort |
Kieran Seay |
| title |
Mice transgenic for CD4-specific human CD4, CCR5 and cyclin T1 expression: a new model for investigating HIV-1 transmission and treatment efficacy. |
| title_short |
Mice transgenic for CD4-specific human CD4, CCR5 and cyclin T1 expression: a new model for investigating HIV-1 transmission and treatment efficacy. |
| title_full |
Mice transgenic for CD4-specific human CD4, CCR5 and cyclin T1 expression: a new model for investigating HIV-1 transmission and treatment efficacy. |
| title_fullStr |
Mice transgenic for CD4-specific human CD4, CCR5 and cyclin T1 expression: a new model for investigating HIV-1 transmission and treatment efficacy. |
| title_full_unstemmed |
Mice transgenic for CD4-specific human CD4, CCR5 and cyclin T1 expression: a new model for investigating HIV-1 transmission and treatment efficacy. |
| title_sort |
mice transgenic for cd4-specific human cd4, ccr5 and cyclin t1 expression: a new model for investigating hiv-1 transmission and treatment efficacy. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2013 |
| url |
https://doaj.org/article/81ace1bf4b8b412ab2052854cde06e08 |
| work_keys_str_mv |
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| _version_ |
1718422983226163200 |