Using Computational Modeling To Optimize the Design of Antibodies That Trap Viruses in Mucus

Abstract

Immunoglobulin G (IgG) antibodies that trap viruses in cervicovaginal mucus (CVM) via adhesive interactions between IgG-Fc and mucins have recently emerged as a promising strategy to block vaginally transmitted infections. The array of IgG bound to a virus particle appears to trap the virus by making multiple weak affinity bonds to the fibrous mucins that form the mucus gel. However, the antibody characteristics that maximize virus trapping and minimize viral infectivity remain poorly understood. Toward this goal, we developed a mathematical model that takes into account physiologically relevant spatial dimensions and time scales, binding, and unbinding rates between IgG and virions and between IgG and mucins, as well as the respective diffusivities of virions and IgG in semen and CVM. We then systematically explored the IgG-antigen and IgG-mucin binding and unbinding rates that minimize the flux of infectious HIV arriving at the vaginal epithelium. Surprisingly, contrary to common intuition that infectivity would drop monotonically with increasing affinities between IgG and HIV, and between IgG and mucins, our model suggests maximal trapping of HIV and minimal flux of HIV to the epithelium are achieved with IgG molecules that exhibit (i) rapid antigen binding (high k_on) rather than very slow unbinding (low k_off), that is, high-affinity binding to the virion, and (ii) relatively weak affinity with mucins. These results provide important insights into the design of more potent "mucotrapping" IgG for enhanced protection against vaginally transmitted infections. The model is adaptable to other pathogens, mucosal barriers, geometries, and kinetic and diffusional effects, providing a tool for hypothesis testing and producing quantitative insights into the dynamics of immune-mediated protection.

Keywords: HIV; IgG; cervicovaginal mucus; mucin; mucosal immunity; sexually transmitted infections.

Figure 1

Schematic of our model that captures the dynamics of HIV from seminal fluid diffusing across a cervicovaginal mucus (CVM) layer containing HIV-binding IgG to reach the underlying vaginal epithelium. To reduce infection, IgG must bind to HIV in sufficient quantities to neutralize or to trap the virions in mucus before HIV virions successfully penetrate CVM. Our model captures the tandem effects of IgG–antigen binding kinetics (k_on, k_off) as well as IgG–mucin interactions (m_on, m_off).

Figure 2

Distribution of time HIV virions spend freely diffusing or associated with mucins in CVM containing 1 µg/mL NIH45-46 with different affinity to mucins, ranging from no affinity at α = 1 to very strong affinity at α = 0.001. To minimize bias toward virions with no surface-bound IgG undergoing free diffusion, Abs are allowed to accumulate on HIV for 30 min first prior to measuring the time of free diffusion or association with mucins for the subsequent 90 min.

Figure 3

Predicted trapping potency and protection by 5 and 10 µg/mL NIH45-46 with varying affinity to mucins as characterized by α: (A) predicted fraction of HIV load initially in semen that can diffuse across CVM containing NIH45-46 over the first 2 h post-deposition; (B) average number of NIH45-46 bound to HIV arriving at the vaginal epithelium (values <1 represent HIV virions that arrive at the vaginal epithelium without any bound NIH45-46); (C, D) extent of NIH45-46-mediated protection, as quantified by infectivity relative to (C) no NIH45-46 present in CVM or (D) the same amount of NIH45-46 present but without any affinity to mucins.

Figure 4

Phase diagrams mapping the predicted trapping potency and protection as a function of NIH45-46 concentration in CVM and IgG affinity to mucins as characterized by α: (A) fraction of HIV load initially in semen that can diffuse across CVM containing NIH45-46 over the first 2 h post-deposition; (B) average number of Ab-free Env trimers on HIV arriving at the vaginal epithelium; (C, D) extent of NIH45-46-mediated protection, as quantified by infectivity relative to (C) no NIH45-46 present in CVM or (D) the same amount of NIH45-46 present but without any affinity to mucins.

Figure 5

Phase diagrams mapping the predicted trapping potency and protection as a function of NIH45-46 unbinding kinetics from HIV virions (k_off) as well as accumulation kinetics on HIV virions, which is influenced by both the local NIH45-46 concentrations and the binding rate (k_on): (A) fraction of HIV load initially in semen that can diffuse across CVM containing NIH45-46 over the first 2 h post-deposition; (B) average number of Ab-free Env trimers on HIV arriving at the vaginal epithelium; (C, D) extent of NIH45-46-mediated protection, as quantified by infectivity relative to (C) no NIH45-46 present in CVM or (D) the same amount of NIH45-46 present but without any affinity to mucins.