Generation of an HIV-1-resistant immune system with CD34+ hematopoietic stem cells transduced with a triple-combination anti-HIV lentiviral vector

Jon E. Walker, Rachel X. Chen, Jeannine McGee, Catherine Nacey, Richard B Pollard, Mehrdad Abedi, Gerhard Bauer, Jan Nolta, Joseph S Anderson

Research output: Contribution to journalArticlepeer-review

67 Scopus citations


HIV gene therapy has the potential to offer an alternative to the use of current small-molecule antiretroviral drugs as a treatment strategy for HIV-infected individuals. Therapies designed to administer HIV-resistant stem cells to an infected patient may also provide a functional cure, as observed in a bone marrow transplant performed with hematopoietic stem cells (HSCs) homozygous for the CCR5-Δ32-bp allele. In our current studies, preclinical evaluation of a combination anti-HIV lentiviral vector was performed, in vivo, in humanized NOD-RAG1-/- IL2rγ-/- knockout mice. This combination vector, which displays strong preintegration inhibition of HIV-1 infection in vitro, contains a human/rhesus macaque TRIM5α isoform, a CCR5 short hairpin RNA (shRNA), and a TAR decoy. Multilineage hematopoiesis from anti-HIV lentiviral vector-transduced human CD34+ HSCs was observed in the peripheral blood and in various lymphoid organs, including the thymus, spleen, and bone marrow, of engrafted mice. Anti-HIV vector-transduced CD34+ cells displayed normal development of immune cells, including T cells, B cells, and macrophages. The anti-HIV vector-transduced cells also displayed knockdown of cell surface CCR5 due to the expression of the CCR5 shRNA. After in vivo challenge with either an R5-tropic BaL-1 or X4-tropic NL4-3 strain of HIV-1, maintenance of human CD4+ cell levels and a selective survival advantage of anti-HIV gene-modified cells were observed in engrafted mice. The data provided from our study confirm the safety and efficacy of this combination anti-HIV lentiviral vector in a hematopoietic stem cell gene therapy setting for HIV and validates its potential application in future clinical trials.

Original languageEnglish (US)
Pages (from-to)5719-5729
Number of pages11
JournalJournal of Virology
Issue number10
StatePublished - May 2012

ASJC Scopus subject areas

  • Immunology
  • Virology


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