Hope: Antibody-Mucus Interactions
The environment in which HIV vaginal transmission takes place is unique and often cannot be fully appreciated with
in vitro studies. Unlike tissue culture cells, HIV target cells in the vaginal mucosa (largely CD4+ T-cells and macrophages) are protected by epithelial barriers. These barriers are further protected by a mucus layer with properties that have evolved to protect the underlying mucosal epithelial barriers from pathogens. Mucus changes its consistency during the menstrual cycle and is modulated by pH in such a way that the normal vaginal flora, which is acidic, and semen, which is basic, may also play a role in protection from HIV infection. The potential contribution of mucus has not yet been considered in HIV vaccine development.
This research of the CAVD team has generated data demonstrating that antibodies can tightly associate with the mucus in the female reproductive tract (FRT). The emerging picture is that modifications of antibodies, including the antibody glycotype, can direct the binding to specific mucins. Antibody tethering to the large matrix of mucins, which form mucus, will significantly alter the diffusion and distribution of HIV within the FRT during exposure, thus slowing or trapping the virus in mucus, which reduces the opportunity to initiate transmission. Defining the mechanisms directing antibody-binding interactions with mucins will lead to the ability to identify vaccine responses optimized to trap HIV within mucus. With the support of a recent supplement to the project, the team is currently working to test the hypothesis that mucin-associated antibodies will have enhanced ability to decrease vaginal transmission in a rhesus macaque challenge model.
Dr. Hope has assembled a multidisciplinary team consisting of labs in the US and Thailand. It includes expertise in cell and molecular biology, structure and function of antibodies, human reproductive biology, molecular modeling, polymer chemistry, and clinicians experienced in mucosal sampling in natural infection and vaccine trials. The institutions involved are Northwestern University, the Ragon Institute, Duke University, Tulane University and the Henry Jackson Foundation/Military HIV Research Program and their collaborators in Thailand.
The goal for this study is to better understand the capacity of mucus-trapping antibodies to block HIV and the feasibility of eliciting mucus tethering antibodies with vaccines. This group also has the potential to develop a new high throughput, low cost, standardized platform for evaluating the mucus barrier more widely. This could benefit future research on natural and vaccine-induced defenses against other sexually transmitted infections; some of them are important co-factors for HIV infection.
1. Validate mucus transport assay and determine the characteristics of antibodies associated with optimal inhibition of transport in mucus.
2. Determine the characteristics of antibody responses in HIV infected women.
a. Determine if responses generated in cervical/vaginal mucus in the RV305 and RV306 trials can decrease HIV transport.
b. Define the antibody characteristics associated with the best responses observed in the RV305 and RV306 trials.
3. Determine how mucus composition changes during the menstrual cycle and how changes influence the interaction of HIV-antibody complexes.
4. Determine if MUC16 targeted antibodies provide protection from vaginal challenge.