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

Article

关键词: IMMUNODEFICIENCY-VIRUS TYPE-1;    FUSION INHIBITOR T-20;    TYROSINE SULFATION;    N-TERMINUS;    POTENT NEUTRALIZATION;    ENVELOPE GLYCOPROTEIN;    BINDING-SITE;    SOLUBLE CD4;    HIV-1 GP120;    ANTIBODY;   

DOI  :  10.1038/nature14264

来源: SCIE

【 摘 要 】

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)(1,2). However, even the best bNAbs neutralize 10-50% of HIV-1 isolates inefficiently (80% inhibitory concentration (IC80) > 5 mu g ml(-1)), suggesting that high concentrations of these antibodies would be necessary to achieve general protection(3-6). Here we show that eCD4-Ig, a fusion ofCD4-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 mu g 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 mu g ml(-1) of fully functional rhesuseCD4-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.

【 授权许可】

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