Abstract
Eliciting broadly neutralizing antibodies (bnAb) in cervicovaginal mucus (CVM) represents a promising “first line of defense” strategy to reduce vaginal HIV transmission. However, it remains unclear what levels of bnAb must be present in CVM to effectively reduce infection. We approached this complex question by modeling the dynamic tally of bnAb coverage on HIV. This analysis introduces a critical, timescale-dependent competition: to protect, bnAb must accumulate at sufficient stoichiometry to neutralize HIV faster than virions penetrate CVM and reach target cells. We developed a model that incorporates concentrations and diffusivities of HIV and bnAb in semen and CVM, kinetic rates for binding (kon) and unbinding (koff) of select bnAb, and physiologically relevant thicknesses of CVM and semen layers. Comprehensive model simulations lead to robust conclusions about neutralization kinetics in CVM. First, due to the limited time virions in semen need to penetrate CVM, substantially greater bnAb concentrations than in vitro estimates must be present in CVM to neutralize HIV. Second, the model predicts that bnAb with more rapid kon, almost independent of koff, should offer greater neutralization potency in vivo. These findings suggest the fastest arriving virions at target cells present the greatest likelihood of infection. It also implies the marked improvements in in vitro neutralization potency of many recently discovered bnAb may not translate to comparable reduction in the bnAb dose needed to confer protection against initial vaginal infections. Our modeling framework offers a valuable tool to gaining quantitative insights into the dynamics of mucosal immunity against HIV and other infectious diseases.
Highlights
During vaginal transmission of HIV-1, virions in semen must traverse the thin layer of cervicovaginal mucus (CVM) coating the vaginal epithelium before they can encounter and potentially infect target cells
Using previous measurements of HIV mobility and Ab diffusivities in human genital secretions, estimates of CVM thickness, and binding affinities for different bnAb based on surface plasmon resonance (SPR) measurements, we model the minimum Ab levels in CVM necessary to achieve 50% and 80% coverage of the HIV Env spikes before HIV virions can reach the vaginal epithelium
Based on published measurements of bnAb affinity to gp120/gp140 trimers, our model predicts that many monoclonal bnAb, at IC50 and IC80 levels measured in vitro, are likely unable to comparably neutralize most HIV strains within the time scale of virion diffusion through the CVM layer
Summary
During vaginal transmission of HIV-1, virions in semen must traverse the thin layer of cervicovaginal mucus (CVM) coating the vaginal epithelium before they can encounter and potentially infect target cells (lymphocytes, macrophages, dendritic cells and Langerhans cells). In women with healthy vaginal microflora, lactobacilli secrete substantial levels of lactic acid, producing an acidic (pH ,3.5–4) environment that inactivates leukocytes within minutes [3]. Few immune cells capable of opsonization and antibody-dependent cell-mediated cytotoxicity (ADCC) are present in healthy CVM secretions, which exhibit limited complement activity [4,5,6]. Neutralization, a process in which secreted or topically-applied Ab engage the gp120/gp trimeric glycoproteins (Env) on HIV at sufficient stoichiometry to preclude their attachment to target cells, is generally thought to be a critical component of sterilizing immunity against initial HIV infections in the vagina [7]. Effective neutralization in the vaginal lumen that directly reduces the rates of acquiring initial infections, rather than attempting to clear infections, may be especially important since HIV infections remain difficult to cure once established
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