HIV suppression efficacy of AAV-bNAb immunotherapy is determined by antibody escapability 3633

Abstract Description The HIV pandemic persists despite efforts to find a cure, and while current therapies are effective, their success relies on strict adherence. Broadly neutralizing antibodies (bNAbs) are a promising alternative, but their implementation is undermined by the need for repeated injections and viral escape. A single IM injection of adeno-associated viral (AAV) vectors encoding for bNAbs results in long-lived expression of the antibody, preventing HIV transmission in different animal models. However, its efficacy in established infections requires further study. To assess this, humanized mice were infected with HIV and then injected with AAVs expressing different bNAbs. For over six months, blood samples were collected to measure antibody levels and to perform deep sequencing of the HIV envelope. AAV-VRC07 suppressed HIV in half of the mice, and HIV sequences from non-suppressed mice displayed conserved escape routes. The efficacy of bNAbs delivered as Vectored ImmunoTherapy (VIT) was dependent on the trade-off between fitness cost and neutralization resistance of mutations, which we defined as escapability. To test this framework, we reduced viral fitness with an ART-based regimen and then administered AAV-VRC07, achieving complete suppression in all mice. Our data suggests that escapability is a key determinant to be harnessed against HIV, as efficacy in vivo correlated with the difficulty of bNAb escape routes rather than the antibody potency. Funding Sources NIH Research Grants R01AI174875, R01AI174276, and NIDA Avenir New Innovator Award DP2DA040254. Topic Categories Vaccines and Immunotherapy (VAC)