Kinetic Rates of Antibody Binding Correlate with Neutralization Sensitivity of Variant Simian Immunodeficiency Virus Strains

Abstract

Increasing evidence suggests that an effective AIDS vaccine will need to elicit both broadly reactive humoral and cellular immune responses. Potent and cross-reactive neutralization of simian immunodeficiency virus (SIV) and human immunodeficiency virus type 1 (HIV-1) by polyclonal and monoclonal antibodies is well documented. However, the mechanisms of antibody-mediated neutralization have not been defined. The current study was designed to determine whether the specificity and quantitative properties of antibody binding to SIV envelope proteins correlate with neutralization. Using a panel of rhesus monoclonal antibodies previously characterized for their ability to bind and neutralize variant SIVs, we compared the kinetic rates and affinity of antibody binding to soluble envelope trimers by using surface plasmon resonance. We identified significant differences in the kinetic rates but not the affinity of monoclonal antibody binding to the neutralization-sensitive SIV/17E-CL and neutralization-resistant SIVmac239 envelope proteins that correlated with the neutralization sensitivities of the corresponding virus strains. These results suggest for the first time that neutralization resistance may be related to quantitative differences in the rates but not the affinity of the antibody-envelope interaction and may provide one mechanism for the inherent resistance of SIVmac239 to neutralization in vitro. Further, we provide evidence that factors in addition to antibody binding, such as epitope specificity, contribute to the mechanisms of neutralization of SIV/17E-CL in vitro. This study will impact the method by which HIV/SIV vaccines are evaluated and will influence the design of candidate AIDS vaccines capable of eliciting effective neutralizing antibody responses.

Killing Kinetics of Simian Immunodeficiency Virus-Specific CD8+ T Cells: Implications for HIV Vaccine Strategies

“…Several potentially effective cellular immune responses have been identified in live-attenuated SIV-vaccinated animals and subjects with attenuated HIV-1 strains, such as the induction of SIV-specific CD4 ϩ T cells and generation of neutralizing Abs (10,46,47). Nonimmune mechanisms have also been postulated to facilitate the effectiveness of retrovirus in LAV vaccines (48,49).…”

Dissecting the Humoral Immune Response to Simian Immunodeficiency Virus: Mechanisms of Antibody-Mediated Virus Neutralization

“…To accomplish this, we compared properties of rhesus MAb binding to the neutralization-resistant SIVmac239 rgp140 with the neutralization-sensitive SIV/17E-CL rgp140 in kinetic SPR analyses (26). In general, we observed significant differences in the rates of MAb binding between the two envelope proteins with the median association and dissociation rates for the MAbs being one-half log higher to SIVmac239 than was observed for SIV/17E-CL.…”

“…Finally, we identified three competition groups (two of which demonstrated V4 sensitivity) that exhibited potent neutralizing activity against the homologous SIV/17E-CL strain using a standard neutralization assay, monitoring for CPE or p27 antigen at d 10 after infection (24). Recent analysis using a more sensitive assay identified the ability of an additional MAb, 3.11H, to neutralize SIV/17E-CL in vitro (26).…”

“…Using a selected panel of MAbs representing each of the competition groups, we performed real-time binding studies using surface plasmon resonance (SPR) as measured on a Biacore 3000 to determine the kinetics of MAb binding to recombinant, trimeric SIV gp140 proteins (26). Owing to the observed lack of correlation between the ability of MAbs to bind envelope and their ability to neutralize SIV/17E-CL in vitro, we proposed that differences might exist in the binding kinetics between neutralizing and nonneutralizing MAbs that would correlate with the ability of a given MAb to neutralize SIV.…”

“…Specifically, we have identified regions in the V4 loop and, putatively, the coreceptor binding site as those areas targeted by neutralizing antibodies during attenuated SIV infection (unpublished data). Additionally, we have identified binding properties of antibodies that allow us to distinguish between neutralization-sensitive (SIV/17E-CL) and neutralization-resistant (SIVmac239) virus strains (26). We propose that the higher antibody dissociation rate (lower antibody stability) to SIVmac239 envelope may provide CD4 the opportunity to bind and recruit coreceptor, thus initiating the fusion process and evading neutralization even in the presence of antibody (26,38).…”