Harnessing Mucus to Fight Human Immunodeficiency Virus

For many people, the word “mucus” conjures up images of an undesirable, slimy, sticky substance. To scientists such as Dr Samuel Lai, associate professor and director of the pharmacoengineering program at the University of North Carolina’s Eshelman School of Pharmacy in Chapel Hill, the viscoelastic secretions are a potential tool for preventing sexually transmitted infections (STIs). Mucus-producing cells line the lumen of all organs and glands that interact with the external environment.¹ They are ubiquitous in the respiratory, genital, and gastrointestinal tracks, where they continuously secrete mucus. Mucus consists primarily of water but also contains electrolytes, lipids, and proteins, including mucins.^1,2 Mucosal secretions provide lubrication and trap contaminants to keep them from reaching the epithelium.¹ In an interview with Infectious Disease Advisor, Dr Lai explained how he and his colleagues are investigating the role of cervicovaginal mucus (CVM) in preventing transmission of HIV and other STIs.³

Infectious Disease Advisor: Can you describe the role of CVM in protecting the epithelium?

Dr Lai: Mucus is continuously secreted in the cervix; it flows out of the cervical os and coats the vaginal epithelium. Mucus helps lubricate the female reproductive tract and minimizes trauma or damage to the underlying epithelium. Any damage to the tissue makes it easier for viruses to reach and infect specific cells in the epithelium. The epithelial cells closest to the vaginal lumen are typically dead because resident lactobacilli secrete lactic acid, which acidifies the mucus/lumen and kills them. Viruses need to infect live cells, most of which are typically located in the epithelium, and hence are less exposed. Research during the last decade has increasingly shown that mucus can serve as a physical barrier that restricts the diffusion of pathogens such as HIV to the epithelial cells. Another benefit of mucus is that it contains an abundance of innate defense molecules.

Infectious Disease Advisor: How does HIV overcome the mucosal barrier?

Dr Lai: Viruses like HIV are transmitted at the mucosal surface. They are under evolutionary pressure to mutate so that they can successfully penetrate the mucus and infect the underlying cells, which HIV has done. Although the abundance of mucus may increase to fight pathogens, the underlying biochemistry of mucins rarely evolves. It is important to note that HIV is not that potent in terms of causing infection; some research suggests it takes at least 100 sexual encounters [with an HIV-infected partner] for 1 successful transmission. However, we also know that a few, maybe even only 1, live virus particles introduced into the bloodstream consistently cause infection; thus, during any single act of intercourse, the number of HIV particles needed to reach the target cells to cause infection is very low.

Infectious Disease Advisor: Why is the CVM in some women better able to resist the virus?

Dr Lai: In our studies, we have found that Lactobacillus crispatus-dominant microbiota pose a much more stringent physical barrier against HIV diffusion than microbiota predominant with Lactobacillus iners or other polymicrobials such as Gardnerella vaginalis. This ex vivo observation is in good agreement with epidemiologic studies that have shown women who have bacterial vaginosis and intermediate microbiota or, according to more recent studies, women who have Lactobacillus iners-predominant microbiota are at markedly greater risk for acquiring HIV and other STIs. Their risk is 3-fold higher or greater. Although viruses appear to have more difficulty traversing CVM in some women, this does not mean viruses will never break through.

Infectious Disease Advisor: What is the practical application of your findings on CVM and viral transmission?

Dr Lai: Mucus serves as the first battleground in the context of vaginal HIV transmission. We know that even small differences in the barrier properties of mucus can make a big difference. Thus, in theory, reducing the fraction of HIV that can permeate mucus by 50% should reduce transmission by 50%. It is likely that mucus must be reinforced in some manner to form an effective barrier against STIs, including HIV. Reinforcing, but not replacing, the existing mucus barrier may be an effective way to enhance protection.

Infectious Disease Advisor: How might reinforcing the mucosal barrier be accomplished?

Dr Lai: A recent breakthrough is the discovery that specific antibodies can help crosslink viruses to the mucin mesh. This implies that induction of antibody secretion locally into the mucosa or direct delivery of protective antibodies to the mucosa (ie, local passive immunization of the vagina) could reinforce the mucus barrier against STIs. My laboratory and collaborators are interested in the latter approach: topical delivery of protective antibodies. With the rapidly declining costs of antibody production, we believe we can create a cost-effective product for female reproductive health.

Infectious Disease Advisor: What progress have you made so far?

Dr Lai: We have demonstrated in a mouse model that topical delivery of specific antibodies can effectively protect against vaginal herpes transmission. We also have unpublished data suggesting that we could similarly reinforce the mucus barrier against HIV. My colleagues and I are currently developing a vaginal ring that can stably release antibodies for at least 35 days at a time. My laboratory has spun off a startup company called Mucommune, LLC, to facilitate the translational development of this effort.

Infectious Disease Advisor: What is the benefit of this approach for HIV?

Dr Lai: To date, induction of durable, high-titer mucosal immune response has proven to be elusive. With the exception of the human papillomavirus vaccine, we do not have a vaccine against the most common STIs, including HIV. Mucus has long been overlooked in the context of infectious disease. An analogy I like to use is that when it comes to defending the castle against foreign invaders, it is generally better to fight the battle at the walls of the castle, or a more apt analogy when talking about mucus is the moats, than inside the castle’s rooms. Given how quickly HIV can mutate, my team believes blocking HIV transmission directly at the portal of transmission, which is often the vaginal mucosa, may be more effective than relying on systemic mechanisms of protection.

Infectious Disease Advisor: Does this approach have application for other infections?

Dr Lai: What we are doing is applicable not only to HIV but to other STIs and, more broadly, to any infections transmitted at mucosal surfaces. One example might be influenza transmission through the airway mucosa.

References

1. Bansil R, Turner BS. The biology of mucus: composition, synthesis and organization. Adv Drug Deliv Rev. 2018;124:3-15.
2. Mall AS, Habte H, Mthembu Y, Peacocke J, de Beer C. Mucus and mucins: do they have a role in the inhibition of the human immunodeficiency virus?Virol J. 2017;14(1):192.
3. Nunn KL, Wang YY, Harit D, et al. Enhanced trapping of HIV-1 by human cervicovaginal mucus is associated with Lactobacillus crispatus-dominant microbiota. MBio. 2015;6(5):e01084-15.