当然，腺相关病毒载体的应用也存在明显障碍。在人和猴体内，腺相关病毒递送的抗体会引起抗体反应，几乎全部由抗体的可变区引起，而可变区正是抗体有效对抗HIV病毒的特异区段，已有人体内递送的HIV单抗由于ADA效应几乎无法检出的报道 （Jefferys, R. HIV vaccine update: the ‘‘Miami macaque’’ as proof-ofconcept breakthrough? 2018）。由此后续还需降低ADA效应、提高递送效率，是该方法进一步应用前急需解决的问题。
DOI:10.1016/j.immuni.2019.02.005
Highlights
Chronically SHIV-infected macaques were treated with AAV-delivered bnAbs
Long-term virologic suppression is possible with AAV-delivered antibodies
A functional cure was achieved in one SHIV-infected macaque
Development of host-generated anti-antibodies limited treatment effectiveness
Summary
Long-term delivery of anti-HIV monoclonal antibodies (mAbs) using adeno-associated virus (AAV) vectors holds promise for the prevention and treatment of HIV infection. We describe a therapy trial in which four rhesus monkeys were infected with SHIV-AD8 for 86 weeks before receiving the AAV-encoded mAbs 3BNC117, 10-1074, and 10E8. Although anti-drug antibody (ADA) responses restricted mAb delivery, one monkey successfully maintained 50–150 μg/mL of 3BNC117 and 10-1074 for over 2 years. Delivery of these two mAbs to this monkey resulted in an abrupt decline in plasma viremia, which remained undetectable for 38 successive measurements over 3 years. We generated two more examples of virologic suppression using AAV delivery of a cocktail of four mAbs in a 12-monkey study. Our results provide proof of concept for AAV-delivered mAbs to produce a “functional cure.” However, they also serve as a warning that ADAs may be a problem for practical application of this approach in humans.
