title: HIV latency in the humanized BLT mouse.
abstract: Even after extended treatment with powerful antiretroviral drugs, HIV is not completely eliminated from infected individuals. Latently infected CD4(+) T cells constitute one reservoir of replication-competent HIV that needs to be eliminated to completely purge virus from antiretroviral drug-treated patients. However, a major limitation in the development of therapies to eliminate this latent reservoir is the lack of relevant in vivo models that can be used to test purging strategies. Here, we show that the humanized BLT (bone marrow-liver-thymus) mouse can be used as both an abundant source of primary latently infected cells for ex vivo latency analysis and also as an in vivo system for the study of latency. We demonstrate that over 2% of human cells recovered from the spleens of HIV-infected BLT mice can be latently infected and that this virus is integrated, activation inducible, and replication competent. The non-tumor-inducing phorbol esters prostratin and 12-deoxyphorbol-13-phenylacetate can each induce HIV ex vivo from these latently infected cells, indicating that this model can be used as a source of primary cells for testing latency activators. Finally, we show activation-inducible virus is still present following suppression of plasma viral loads to undetectable levels by using the antiretroviral drugs zidovudine, indinavir sulfate, and didanosine, demonstrating that this model can also be used to assess the in vivo efficacy of latency-purging strategies. Therefore, the HIV-infected BLT mouse should provide a useful model for assessment of HIV latency activators and approaches to eliminate persistent in vivo HIV reservoirs.
authors.affiliation: Department of Medicine, Division of Hematology and Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Marsden
authors.forename: Michael
authors.initials: M
authors.lastname: Kovochich
authors.forename: Nuttee
authors.initials: N
authors.lastname: Suree
authors.forename: Saki
authors.initials: S
authors.lastname: Shimizu
authors.forename: Roshni
authors.initials: R
authors.lastname: Mehta
authors.forename: Ruth
authors.initials: R
authors.lastname: Cortado
authors.forename: Gregory
authors.initials: G
authors.lastname: Bristol
authors.forename: Dong Sung
authors.initials: DS
authors.lastname: An
authors.forename: Jerome A
authors.initials: JA
authors.lastname: Zack
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology; D001853:Bone Marrow / Q000821:virology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000821:virology; D004195:Disease Models, Animal; D006678:HIV / Q000187:drug effects / Q000502:physiology*; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D006801:Humans; D008099:Liver / Q000821:virology*; D051379:Mice; D016513:Mice, SCID; D013950:Thymus Gland / Q000821:virology*; D019562:Viral Load / Q000187:drug effects; D014775:Virus Activation / Q000187:drug effects; D017735:Virus Latency / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents
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