Multilineage polyclonal engraftment of Cal-1 gene-modified cells and in vivo selection after SHIV infection in a nonhuman primate model of AIDS

CW Peterson, KG Haworth, BP Burke… - … Therapy-Methods & …, 2016 - cell.com
CW Peterson, KG Haworth, BP Burke, P Polacino, KK Norman, JE Adair, SL Hu, JS Bartlett…
Molecular Therapy-Methods & Clinical Development, 2016cell.com
We have focused on gene therapy approaches to induce functional cure/remission of HIV-1
infection. Here, we evaluated the safety and efficacy of the clinical grade anti-HIV lentiviral
vector, Cal-1, in pigtailed macaques (Macaca nemestrina). Cal-1 animals exhibit robust
levels of gene marking in myeloid and lymphoid lineages without measurable adverse
events, suggesting that Cal-1 transduction and autologous transplantation of hematopoietic
stem cells are safe, and lead to long-term, multilineage engraftment following myeloablative …
We have focused on gene therapy approaches to induce functional cure/remission of HIV-1 infection. Here, we evaluated the safety and efficacy of the clinical grade anti-HIV lentiviral vector, Cal-1, in pigtailed macaques (Macaca nemestrina). Cal-1 animals exhibit robust levels of gene marking in myeloid and lymphoid lineages without measurable adverse events, suggesting that Cal-1 transduction and autologous transplantation of hematopoietic stem cells are safe, and lead to long-term, multilineage engraftment following myeloablative conditioning. Ex vivo, CD4+ cells from transplanted animals undergo positive selection in the presence of simian/human immunodeficiency virus (SHIV). In vivo, Cal-1 gene-marked cells are evident in the peripheral blood and in HIV-relevant tissue sites such as the gastrointestinal tract. Positive selection for gene-marked cells is observed in blood and tissues following SHIV challenge, leading to maintenance of peripheral blood CD4+ T-cell counts in a normal range. Analysis of Cal-1 lentivirus integration sites confirms polyclonal engraftment of gene-marked cells. Following infection, a polyclonal, SHIV-resistant clonal repertoire is established. These findings offer strong preclinical evidence for safety and efficacy of Cal-1, present a new method for tracking protected cells over the course of virus-mediated selective pressure in vivo, and reveal previously unobserved dynamics of virus-dependent T-cell selection.
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