Efficient transduction of human hematopoietic repopulating cells with a chimeric HIV1-based vector including SIV capsid.

ABSTRACT: Innate immune factors, such as TRIM5? and cyclophilin A (CypA), act as a major restriction factor of retroviral infection among species. When HIV1 infects human cells, HIV1 capsid binds to human CypA to escape from human TRIM5? restriction. However, in rhesus cells, the mismatch between HIV1 capsid and rhesus CypA is recognized by rhesus TRIM5? to reduce HIV1 infectivity through proteasomal degradation. To circumvent this block, we previously developed a chimeric HIV1 vector (?HIV) that substituted HIV1 capsid with SIV capsid, and it significantly increased transduction efficiency for nonhuman primate cells. In this study, we evaluated whether the ?HIV vector efficiently transduces human cells, and the transduction efficiency might increase by a CypA inhibitor (cyclosporine) and a proteasome inhibitor (MG132). The ?HIV vector could transduce human CD34? cells, as efficiently as the HIV1 vector, in vitro and in xenograft mice, even in the mismatch between SIV capsid and human CypA. Cyclosporine decreased transduction efficiency with the HIV1 vector, whereas it slightly increased transduction efficiency with the ?HIV vector in human CD34? cells. MG132 increased transduction efficiency with both ?HIV and HIV1 vectors in the same manner. However, MG132 was toxic to human CD34? cells at high concentrations, and both drugs had a small range of effective dosage. These findings demonstrate that both ?HIV and HIV1 vectors have similar transduction efficiency for human hematopoietic repopulating cells, suggesting that the ?HIV vector escapes from TRIM5? restriction, which is independent of human CypA.

SUBMITTER: Uchida N 

PROVIDER: S-EPMC6480307 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature