Inhibition of In Vivo HIV Infection in Humanized Mice by Gene Therapy of Human Hematopoietic Stem Cells with a Lentiviral Vector Encoding a Broadly Neutralizing Anti-HIV Antibody
| Autor: | Jian Hua Zheng, Aviva Joseph, Renate Kunert, Gabriela Stiegler, Ken Chen, Monica Dutta, Harris Goldstein, Cindy Chen, Antonia Follenzi |
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| Rok vydání: | 2010 |
| Předmět: |
Genetic enhancement
Genetic Vectors Immunology HIV Infections Mice SCID Antibodies Viral Microbiology Viral vector Mice Immune system Mice Inbred NOD Virology Animals Humans Neutralizing antibody biology Lentivirus virus diseases Genetic Therapy Viral Load Hematopoietic Stem Cells biology.organism_classification Antibodies Neutralizing Transplantation Insect Science HIV-1 Lentivirus Infections biology.protein Pathogenesis and Immunity Immunotherapy Stem cell Antibody Spleen |
| Zdroj: | Journal of Virology. 84:6645-6653 |
| ISSN: | 1098-5514 0022-538X |
| DOI: | 10.1128/jvi.02339-09 |
| Popis: | Due to the inherent immune evasion properties of the HIV envelope, broadly neutralizing HIV-specific antibodies capable of suppressing HIV infection are rarely produced by infected individuals. We examined the feasibility of utilizing genetic engineering to circumvent the restricted capacity of individuals to endogenously produce broadly neutralizing HIV-specific antibodies. We constructed a single lentiviral vector that encoded the heavy and light chains of 2G12, a broadly neutralizing anti-HIV human antibody, and that efficiently transduced and directed primary human B cells to secrete 2G12. To evaluate the capacity of this approach to provide protection from in vivo HIV infection, we used the humanized NOD/SCID/γ c null mouse model, which becomes populated with human B cells, T cells, and macrophages after transplantation with human hematopoietic stem cells (hu-HSC) and develops in vivo infection after inoculation with HIV. The plasma of the irradiated NOD/SCID/γ c null mice transplanted with hu-HSC transduced with the 2G12-encoding lentivirus contained 2G12 antibody, likely secreted by progeny human lymphoid and/or myeloid cells. After intraperitoneal inoculation with high-titer HIV-1 JR-CSF , mice engrafted with 2G12-transduced hu-HSC displayed marked inhibition of in vivo HIV infection as manifested by a profound 70-fold reduction in plasma HIV RNA levels and an almost 200-fold reduction in HIV-infected human cell numbers in mouse spleens, compared to control hu-HSC-transplanted NOD/SCID/γ c null mice inoculated with equivalent high-titer HIV-1 JR-CSF . These results support the potential efficacy of this new gene therapy approach of using lentiviral vectors encoding a mixture of broadly neutralizing HIV antibodies for the treatment of HIV infection, particularly infection with multiple-drug-resistant isolates. |
| Databáze: | OpenAIRE |
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