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

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)1,2. However even the best bNAbs neutralize 10–50% of HIV-1 isolates inefficiently (IC80 > 5 μg/ml), suggesting that high concentrations of these antibodies would be necessary to achieve general protection3–6. 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 IC50 < 0.05 μg/ml). 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 SIV 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 to 77 μg/ml of fully functional rhesus eCD4-Ig for 40 weeks, and these macaques were protected from multiple 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.

Simian Immunodeficiency Virus SIVmac239, but Not SIVmac316, Binds and Utilizes Human CD4 More Efficiently than Rhesus CD4

“…We further show that a key determinant of the greater neutralization by human CD4-Ig is residue 39, an asparagine in human CD4 but an isoleucine in the rhesus ortholog. This observation is consistent with previous reports demonstrating that this CD4 residue can also account for the ability of various SHIVs to utilize human CD4 more efficiently than rhesus CD4 (13,15). While it is not unexpected that SHIVs, whose Envs are derived from HIV-1, would utilize human CD4 more efficiently, SIV's preference for human CD4 requires greater explanation.…”

“…We have previously observed that huCD4-Ig more efficiently neutralizes various HIV-1 Envs than does a CD4-Ig variant with rhesus CD4 and Fc domains (15). As suggested by Humes et al (13), we also observed that introduction of human CD4 asparagine 39 into this rhesus CD4-Ig construct neutralized HIV-1 isolates with efficiencies similar to huCD4-Ig (15). To focus our current studies on the CD4 domains of these constructs, here we used a common human IgG1 Fc domain for huCD4-Ig, rhCD4-Ig, and rhCD4-Ig variants.…”

Generation of a neutralization-resistant CCR5 tropic simian/human immunodeficiency virus (SHIV-MK38) molecular clone, a derivative of SHIV-89.6

“…In this study, we showed that the neutralization-resistant R5 tropic SHIV-MK38#818 molecular clone derived from SHIV-KS661 can cause stably persistent infection with high viral load via intrarectal inoculation despite the immune responses that occurred in the host. Currently, SHIV AD8 , categorized as a tier 2 neutralization-resistant phenotype, is widely used as a SHIV challenge virus for a variety of vaccine developments (Nishimura et al, 2010;Shingai et al, 2012Shingai et al, 2013;Gardner et al, 2015;Francica et al, 2015). However, use of SHIV AD8 as the only challenge virus is very risky for precise evaluation in vaccine candidates and anti-HIV-1 neutralizing antibodies.…”

HIV Genome-Wide Protein Associations: a Review of 30 Years of Research

“…During viral budding, this aggregation, however, prohibits the packaging of Env into viral particles (12)(13)(14)(15)(16)(17). As of today, a large number of antibodies (e.g., VRC01) that target CD4-binding sites in GP120 have been demonstrated to have a broad and potent activity of neutralization (440)(441)(442)(443)(444)(445)(446). Many antiviral agents (e.g., NBD556) against the GP120-CD4 interaction are under investigation (447)(448)(449).…”