Development of highly neutralizing nanobodies against HIV-1

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HIV-1 and -2 are lentiviruses that cause acquired immunodeficiency syndrome (AIDS) in humans. To date, no effective vaccine has been developed and according to the World Health Organization nearly 40 million people are infected with HIV across the world. Because preventive measures and treatments are not widely available, AIDS is the leading cause of death in areas such as Sub Saharan Africa. There is therefore an urgent need to develop efficient methods, including vaccines, to prevent HIV infection in susceptible populations. With mixed results, several drugs have been tested in the past decade for use as topical microbicides to prevent HIV entry. However, these approaches require drug delivery through vaginal rings, gels, films or enemas, which are not practical treatments in poor areas of the world. An intriguing alternative is the use of gastrointestinal and genital tract bacteria as in vivo delivery vectors for anti-viral peptides. For instance, Lactobacillus delivery of HIV-1 entry inhibitors markedly reduced the incidence of SIV infection in rhesus monkeys. A similar strategy was used to block Clostridium difficile toxins by means of camelid heavy chain only antibodies. V(D)J domains from these antibodies, also known as nanobodies, are particularly suited for the development of microbicides because they are readily secreted by commensal bacteria, are resistant to denaturation under varied pH conditions, and can easily penetrate the cervicovaginal mucosa. In addition, because of their small size, nanobodies can be developed against antigen crevices such as HIV glycan-shielded spikes, which are challenging targets for bulkier conventional antibodies. Nanobodies can also be humanized with relative ease, a strategy that reduces their immunogenicity in clinical trials. This project proposes the development of highly neutralizing anti-HIV nanobodies for potential use as microbicides or in in vivo therapies. Furthermore, we lay out an approach to produce nanobodies in mice with the goal of developing nanobody-based therapies against HIV-1 and other human pathogens.