The Sequencing and Viral Evolution Core (Core B) will support deep sequencing and bioinformatic analysis of samples from the U19 consortium. Two types of samples will be analyzed. 1) The core will analyze sites of vector integration longitudinally following transduction with lentiviral vectors, with the goals of tracking the behavior of cell populations and scanning for adverse events. So far there have been no examples of transformation associated with integration of a lentiviral vector in T-cells, so we do not expect to detect any adverse events. The integration site tracking will focus primarily on reporting on the number of clones that give rise to transduced cells, and their longitudinal behavior. 2) The core will track HIV evolution in the presence of selective pressures from the C34-CXCR4 and CD4-CAR/CD8-CAR interventions by deep sequencing of HIV env in longitudinal samples. This study will be coupled with targeted analysis of escape mutations, providing specific targets to analyze. Any candidate escape mutations detected will be provided to the projects for follow up. Specific interactions with the four projects include the following. Core B will 1) characterize lentiviral integration sites as part of the safety monitoring of the Phase I clinical trial (Project 1); 2) work with Projects 1 and 2 to study resistance to X4-C34 (deep sequencing of virus), first in the humanized mouse model and then in patients; 3) work with Projects 2 and 3 to study HIV-1 resistance to CD4-CAR based therapy in the presence and absence of C34-CXCR4 modification; and 4) work with Project 4 to study persistence of gene-modified cells.
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