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February 28, 2011

Infusion of Genetically-Modified HIV-Resistant CD4 Cells Show Potential Benefit

We have all seen patients with chronically low and even decreasing CD4 counts despite aviremia on HAART. This may be due to low-level cryptic viral replication in mucosal tissues that deplete progenitor cells, contributing to poor immunologic outcomes. Because CD4 adoptive transfer therapies have shown limited persistence of the infused cells in the past, Jay Lalezari and his coinvestigators hypothesized that gene modification of circulating CD4 cells, using zinc-finger nuclease-mediated CCR5-disrupted CD4 cells, might provide protection against R5 tropic infection with HIV, and lead to a more sustainable CD4 response.

As discussed in an oral presentation today at the 18th Conference on Retroviruses and Opportunistic Infections, six aviremic HIV subjects on HAART with CD4 counts of 200 to 500 cells/mm3 were enrolled in this potentially ground breaking study. Autologous R5-disrupted T cells were expanded ex vivo and then re-infused. Subjects were followed weekly for 1 month and then monthly for 11 months post-infusion. The percentage of R5 disrupted cells in the peripheral blood of the 5 subjects ranged from 1-6% at day 14 and persisted for the duration of follow up. CD4 counts increased in all subjects at day 14 (35 to 1038 cells/mm3) and were sustained at all time points. R5-disrupted cells were detected in the rectal mucosa of all subjects at all assessed time points with levels of R5 disruption approximating that of PB when normalized for CD4 cells within each compartment.

Dr Lalezari and his coinvestigators concluded that using this method, the levels of persistent engraftment on day 90 were 6- to 40-fold greater than previously reported. Homing of these cells to the gut mucosa was observed in all subjects tested, with R5 disruption levels similar to PB suggesting these cells traffic normally. Importantly, increases in total CD4 counts were seen in all 5 subjects at all time points.

Lalezari J, Mitsuyasu R, Deeks S, et al. Successful and Persistent Engraftment of ZFN-M-R5-D Autologous CD4 T Cells (SB-728-T) in Aviremic HIV-infected Subjects on HAART. Presented February 28, 2011, at 18th Conference on Retroviruses and Opportunistic Infections, Boston, MA. Oral Abstract 46.

Source: Reporting from Boston for PRN News: James F Braun, DO