HIV infection remains a major cause of mortality and morbidity despite advances in treatment and prevention. Around 35 million people are infected worldwide, and access to antiretroviral drugs is not guaranteed. New therapies are needed to impact the transmission and pathology of HIV infection and to bring about a long awaited cure. This study will use the novel approach of delivering broadly neutralizing antibodies (bNAb) against the HIV envelope directly to the intestinal mucosa using bioengineered hookworms. Hookworms live and feed in the small intestine, in an ideal location to deliver a molecular payload to both the mucosal surface and the systemic circulation. In heavy infections, hookworms can cause anemia by sucking blood. However, the hookworm Necator americanus is safe and potentially beneficial in low numbers, as demonstrated by several recent clinical trials, and are currently being administered to humans in an FDA-approved study for the development of a hookworm vaccine challenge model by members of our department.
This study intends to exploit the intimate relationship between the feeding hookworm and the gut mucosa for HIV therapy. Broadly neutralizing HIV antibodies would be secreted directly at the mucosal surface to suppress or prevent HIV infection. Hookworms have the advantage of continuous expression over several years, obviating the need for multiple treatments, and unlike viral vectors, the treatment could be discontinued at any time by administering an anthelmintic. This study will address the major roadblock preventing implementation of this novel startegy: the lack of a robust transgenesis protocol for hookworms, and will develop a robust transgenesis protocol, then use it to generate transgenic hookworm strains expressing HIV neutralizing antibodies as proof of concept. The hookworm strains will then be used to infect animals, and monitor the expression and uptake of neutralizing antibodies. If successful, this technology will be useful for future proposals to develop transgenic strains of the human hookworm N. americanus to test in humans.