title: High-Throughput Humanized Mouse Models for Evaluation of HIV-1 Therapeutics and Pathogenesis.
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 intrasplenic 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.
authors.affiliation: Departments of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
authors.forename: Tynisha
authors.initials: T
authors.lastname: Thomas
authors.affiliation: Departments of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
authors.forename: Kieran
authors.initials: K
authors.lastname: Seay
authors.affiliation: Departments of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
authors.forename: Jian Hua
authors.initials: JH
authors.lastname: Zheng
authors.affiliation: Departments of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
authors.forename: Cong
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Ochsenbauer
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.|Birmingham Veterans Affairs Medical Center, Research Service, Birmingham, AL, 35294, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Kappes
authors.affiliation: Departments of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA. harris.goldstein@einstein.yu.edu.|Departments of Pediatrics, Albert Einstein College of Medicine, Forchheimer Building, Room 408, 1300 Morris Park Avenue, Bronx, NY, 10461, USA. harris.goldstein@einstein.yu.edu.
authors.forename: Harris
authors.initials: H
authors.lastname: Goldstein
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D015704:CD4 Antigens / Q000235:genetics; D002460:Cell Line; D056906:Cyclin T / Q000235:genetics; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D057166:High-Throughput Screening Assays / Q000379:methods; D006801:Humans; D008297:Male; D051379:Mice / Q000235:genetics / Q000502:physiology / Q000821:virology; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D019713:Receptors, CCR5 / Q000235:genetics; D014162:Transfection; D019076:Transgenes
chemical_list: D019380:Anti-HIV Agents; C584933:CCR5 protein, human; D015704:CD4 Antigens; D056906:Cyclin T; D019713:Receptors, CCR5
keywords: Antiretroviral treatment; HIV-1; Mouse model