Durable Suppression of Established Transmitted Founder Replication in Infected BLT Humanized Mice by Vectored Immuno Therapy

Abstract

Recent reports in humanized mice and monkeys have found that broadly neutralizing antibodies (bNAbs) can suppress the replication of laboratory strains of HIV and SHIV while bNAb concentration remains high. Vectored ImmunoProphylaxis (VIP) results in long-lived bNAb expression following a single intramuscular {IM) injection of a specialized viral vector, and this approach has been demonstrated as a means of durably suppressing viral load. However, previous reports of VIP-delivered bNAbs for HIV therapy required prior antiretroviral drug therapy to reduce viral load to prevent escape. Methods: Humanized BLT mice were infected IV with the REJO.c transmitted molecular founder strain of HIV. A low dose of combination antiretroviral therapy (ART) was administered to these animals for 5 weeks, followed by a single IM injection of VIP expressing VRC07 or luciferase. Mouse plasma was analyzed by ELISA to determine antibody concentration and by qPCR to determine viral load. Cellular fractions were analyzed by flow cytometry to quantify human CD4 cells over time. After sacrifice, plasma was subjected to a clinically validated ultrasensitive PCR-based viral load assay. Results: We detected viral loads of 10^5 copies/mL in infected mice prior to low-dose ART treatment, which resulted in a transient reduction and rebound to pre-therapy loads. Following VIP administration, we observed a rapid increase in the blood concentration of VRC07. Mice expressing VRC07 exhibited a sharp decline in viral load to undetectable levels and an increase in CD4 cells over four weeks and this effect was sustained for the remaining 8 weeks of the study. In contrast, mice expressing luciferase exhibited increasing viral loads with concomitant decreases in CD4 cells throughout the study. Conclusions: Our results demonstrate that VIP expressing VRC07 is sufficient to suppress actively replicating transmitted founder virus at high viral load and support efforts to move Vectored Immuno Therapy into clinical trials with infected patients.

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