title: Mice transgenic for CD4-specific human CD4, CCR5 and cyclin T1 expression: a new model for investigating HIV-1 transmission and treatment efficacy.
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.
authors.affiliation: Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Kieran
authors.initials: K
authors.lastname: Seay
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Qi
authors.forename: Jian Hua
authors.initials: JH
authors.lastname: Zheng
authors.forename: Cong
authors.initials: C
authors.lastname: Zhang
authors.forename: Ken
authors.initials: K
authors.lastname: Chen
authors.forename: Monica
authors.initials: M
authors.lastname: Dutta
authors.forename: Kathryn
authors.initials: K
authors.lastname: Deneroff
authors.forename: Christina
authors.initials: C
authors.lastname: Ochsenbauer
authors.forename: John C
authors.initials: JC
authors.lastname: Kappes
authors.forename: Dan R
authors.initials: DR
authors.lastname: Littman
authors.forename: Harris
authors.initials: H
authors.lastname: Goldstein
mesh_terms: D000818:Animals; D023241:Antiretroviral Therapy, Highly Active; D001483:Base Sequence; D015704:CD4 Antigens / Q000235:genetics*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D056906:Cyclin T / Q000235:genetics*; D017931:DNA Primers; D005434:Flow Cytometry; D015658:HIV Infections / Q000188:drug therapy* / Q000635:transmission*; D015497:HIV-1; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D019713:Receptors, CCR5 / Q000235:genetics*
chemical_list: C584933:CCR5 protein, human; D015704:CD4 Antigens; D056906:Cyclin T; D017931:DNA Primers; D019713:Receptors, CCR5