Impact of AGT103-T cell and gene therapy on intact HIV proviral reservoirs

OBJECTIVE: To assess the impact of AGT103-T, an autologous CD4 + T-cell and gene therapy, on HIV proviral DNA reservoir. DESIGN: Intact proviral DNA is quantified using the intact proviral DNA assay (IPDA). Here, IPDA was modified and analytically qualified for use in people with HIV (PWH) treated with lentiviral-based therapies and applied to samples from six participants who received AGT103-T. METHODS: Standard IPDA targets overlap with sequences present in lentiviral vectors, including the AGT103-T therapeutic vector, preventing accurate quantification. We developed a modified IPDA that avoids vector interference while preserving detection of intact HIV proviruses by targeting HIV Gag and Nef regions. The assay was qualified for specificity, linearity, and reproducibility using plasmid standards and human DNA. Enriched CD4 + T cells from peripheral blood collected pretreatment, posttreatment, and during analytical treatment interruption in a Phase 1 trial (NCT04561258; NCT05540964) were analyzed. RESULTS: Intact proviral DNA declined in all six participants following AGT103-T treatment and reached below the assay's lower limit of detection by the end of follow-up. In contrast, defective proviral DNA showed variable changes without a consistent decline. CONCLUSIONS: AGT103-T treatment was associated with a reduction in intact HIV proviral DNA within circulating CD4 + T cells. These findings extend prior reports describing positive immune and virologic outcomes in AGT103-T-treated participants during analytical treatment interruption. The modified intact proviral DNA assay enables accurate measurement of the intact HIV reservoir in the context of lentiviral gene therapy and supports continued clinical evaluation of AGT103-T.