Background: Long-term in vivo expression of a broad and potent entry inhibitor could circumvent the need for a conventional HIV-1 vaccine. Adeno-associated virus (AAV) vectors can stably express broadly neutralizing HIV-1 antibodies (bNAbs). However, more than a quarter of HIV-1 isolates are at least partially resistant (IC80 > 5 µg/ml) to even the best bNAbs, suggesting that very high concentrations of these antibodies would be necessary to achieve general protection.Methods: Here we characterize eCD4-Ig, a fusion of CD4-Ig with a small CCR5-mimetic sulfopeptide, and assess AAV-delivery of eCD4-Ig as a means of stably protecting individuals from a new HIV-1 infection. Results: We show that eCD4-Ig binds avidly and cooperatively to the HIV-1 envelope glycoprotein (Env) and is more potent than the best bNAbs (geometric mean IC50 < 0.05 µg/ml). Because eCD4-Ig only binds conserved regions of the Env, it is also much broader than any bNAb. For example, eCD4-Ig neutralized 100% of a diverse panel of neutralization-resistant HIV-1, HIV-2, and SIV isolates with IC80s less than 5 µg/ml, 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 expressed 16-84 µg/ml of fully functional rhesus eCD4-Ig over 32 weeks, and these macaques were protected from multiple challenges with SHIV-AD8 that efficiently infected control macaques. Moreover, eCD4-Ig was markedly less immunogenic than any of four well characterized bNAbs.Conclusions: AAV-expressed eCD4-Ig can function as an effective HIV-1 vaccine alternative.
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