AAV vectors are ideally suited for long-term delivery of a combination of broadly neutralizing antibodies to achieve sterilizing
immunity to HIV. Unfortunately, host immune responses to the delivered
antibody have severely limited the
efficacy. The TLR9 pathway has been identified in initiating adaptive immune responses against AAV and delivered bNAbs. To enhance this strategy, we validated
Hydroxychloroquine, a known
drug inhibitor of the TLR9 pathway, as a pretreatment to AAV delivery to avoid anti-
drug antibody responses. TLR9 signaling inhibition was validated using a HEK-Blue hTLR9 reporter
cell line and CpG stimulation.
Hydroxychloroquine was also validated in a 3-
macaque trial where AAV9-3BNC117 and AAV9-10-1074 were administered along with 3 doses of
hydroxychloroquine once a week starting 1 week before AAV
inoculation. Together, these data suggest that the short-term treatment of
hydroxychloroquine at the time of AAV
inoculation has a meaningful
impact on
tolerance induction to our AAV-delivered bNAbs.