Microbicides in the Pipeline

The antiretrovirals (ARVs) tenofovir and Truvada—a combination of tenofovir and emtricitabine—have received the lion’s share of attention lately for their role in preventing HIV infection, but researchers are experimenting with other ARVs that may also be effective topical pre-exposure prophylaxis (PrEP) agents.

One of those is maraviroc, the first licensed ARV that blocks HIV entry into cells by binding to the CCR5 receptor. Another is a new CCR5 inhibitor known as 5P12-Rantes that is produced by bacterial fermentation. It is expressed as a recombinant protein using Pichia pastoris yeast, making it cheap to produce, said University of Geneva structural biologist Oliver Hartley during a Keystone talk today.
 
The 5P12-Rantes microbicide, which has been shown to completely protect rhesus macaques from vaginal challenge with an R5-tropic virus that combines parts of HIV with simian immunodeficiency virus (SIV), has not been tested in humans yet, but the Microbicide Trials Network and the International Partnership for Microbicides are planning to launch a Phase I trial of a dapivirine/maraviroc vaginal ring later this year. Hartley, who has been involved in the development of the 5P12-Rantes microbicide candidate, said the compound blocks the virus in a different way than maraviroc. “It’s a big molecule, and it may actually sit on top of the (CCR5) receptor and hide it, so the virus can’t see it,” said Hartley.
 
Another microbicide in the pipeline uses genetically engineered microbes as a long-term self-sustaining form of HIV-inhibitor delivery. Researchers who tested a live vaginal protein-based microbicide that introduced the gene for Cyanovirin into Lactobacilli bacteria, which normally live in the vaginal mucosa, reported last year that they found a 63% reduction in acquisition of HIV in Chinese rhesus macaques (see Meeting of the Minds on Mucosal Transmission, IAVI Report, May-June 2010). Laurel Lagenaur, a senior scientist at the California-based company Osel Inc. that developed the microbicide, said at this morning’s Keystone Symposia session on Virus-Specific Microbicides, that the trial was an example of a live anti-HIV microbicide as proof of concept, and based upon the results Osel is now planning to file an Investigational New Drug application with the US Food and Drug Administration and is moving ahead with plans for an array of pre-clinical tests. “We hope to take it to human trials within five years,” said Lagenaur. She also said the microbicide product could conceivably be developed as a mucosally administered boost to an AIDS vaccine.
 
In response to a question from a Keystone attendee, Lagenaur said researchers don’t say for sure whether the Cyanovir protein was what actually provided the protective effect because a Cyanovir-only arm in macaques was not done. Lagenaur said Osel expects to do a trial to determine whether Cyanovir or the bacteria provided the protection. “The question is an academic one, but we would still like to know,” she said.