AAV-expressed eCD4-Ig provides durable protection from multiple SHIV challenges.

TitleAAV-expressed eCD4-Ig provides durable protection from multiple SHIV challenges.
Publication TypeJournal Article
Year of Publication2015
AuthorsGardner MR, Kattenhorn LM, Kondur HR, von Schaewen M, Dorfman T, Chiang JJ, Haworth KG, Decker JM, Alpert MD, Bailey CC, Neale ES, Fellinger CH, Joshi VR, Fuchs SP, Martinez-Navio JM, Quinlan BD, Yao AY, Mouquet H, Gorman J, Zhang B, Poignard P, Nussenzweig MC, Burton DR, Kwong PD, Piatak M, Lifson JD, Gao G, Desrosiers RC, Evans DT, Hahn BH, Ploss A, Cannon PM, Seaman MS, Farzan M
JournalNature
Volume519
Issue7541
Pagination87-91
Date Published03/05/2015
ISSN1476-4687
Abstract

Long-term in vivo expression of a broad and potent entry inhibitor could circumvent the need for a conventional vaccine for HIV-1. Adeno-associated virus (AAV) vectors can stably express HIV-1 broadly neutralizing antibodies (bNAbs). However, even the best bNAbs neutralize 10-50% of HIV-1 isolates inefficiently (80% inhibitory concentration (IC80) > 5 μg ml(-1)), suggesting that high concentrations of these antibodies would be necessary to achieve general protection. Here we show that eCD4-Ig, a fusion of CD4-Ig with a small CCR5-mimetic sulfopeptide, binds avidly and cooperatively to the HIV-1 envelope glycoprotein (Env) and is more potent than the best bNAbs (geometric mean half-maximum inhibitory concentration (IC50) < 0.05 μg ml(-1)). Because eCD4-Ig binds only conserved regions of Env, it is also much broader than any bNAb. For example, eCD4-Ig efficiently neutralized 100% of a diverse panel of neutralization-resistant HIV-1, HIV-2 and simian immunodeficiency virus isolates, including a comprehensive set of isolates resistant to the CD4-binding site bNAbs VRC01, NIH45-46 and 3BNC117. Rhesus macaques inoculated with an AAV vector stably expressed 17-77 μg ml(-1) of fully functional rhesus eCD4-Ig for more than 40 weeks, and these macaques were protected from several infectious challenges with SHIV-AD8. Rhesus eCD4-Ig was also markedly less immunogenic than rhesus forms of four well-characterized bNAbs. Our data suggest that AAV-delivered eCD4-Ig can function like an effective HIV-1 vaccine.

DOI10.1038/nature14264
Alternate JournalNature
PubMed ID25707797
PubMed Central IDPMC4352131
Grant ListHHSN261200800001E / / PHS HHS / United States
P01 AI100263 / AI / NIAID NIH HHS / United States
P01 AI100263 / AI / NIAID NIH HHS / United States
R01 AI058715 / AI / NIAID NIH HHS / United States
R01 AI080324 / AI / NIAID NIH HHS / United States
R01 AI091476 / AI / NIAID NIH HHS / United States
R01 AI091476 / AI / NIAID NIH HHS / United States
RR000168 / RR / NCRR NIH HHS / United States
UM1 AI100663 / AI / NIAID NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
CHAVI-ID: 
1
Cover Picture: