Toward a live microbial microbicide for HIV: Commensal bacteria secreting an HIV fusion inhibitor peptide

An anti-HIV microbicide comes alive

“…Rao et al (2) demonstrate high-level in vitro secretion of the intact fusion peptides, whose neutralizing activities were comparable to those reported for various unfused HR2 peptides. The engineered bacteria were administered to CD-1 mice orally or rectally, and colonization (as measured by fecal bacteria counts) was observed; it was maintained at high levels for up to 12 days, but only if ampicillin was coadministered for selection.…”

“…Rao et al (2) provide proof-ofconcept that a commensal bacterial strain can indeed be genetically engineered to function as a live microbicide factory capable of setting up shop at various regions of the gut mucosa. These promising findings beg the obvious question: Can a useful microbicide based on the Nissle͞HR2 peptide system be developed?…”

“…Others, such as chemokine derivatives (8), block specific interactions of virion gp120 with target cell receptors. The HR2 peptides used by Rao et al (2) represent a sort of hybrid mode: they act by binding to virions, but only after gp120 has engaged the receptors to trigger formation of the gp41 prehairpin intermediate with its HR1 region exposed. Because of their distinct modes of action, these three classes of HIV-inhibitory proteins will likely differ with respect to the anatomical site where they must function (see Fig.…”

“…A battery of promising protein-based HIV inhibitors can potentially be developed (1), but they face serious challenges of high production costs and instability during transport and storage. In a recent issue of PNAS, Rao et al (2) presented an intriguing version of a ''live microbicide'' approach whereby a commensal bacterium is engineered to secrete a potent anti-HIV peptide. When administered orally or as a rectal suppository, the bacteria would colonize the gut mucosa and secrete the peptide in situ, thereby providing protection in advance of exposure hopefully for days, weeks, or even months.…”

“…These sobering results might be explained in part by the extremely high amounts of challenge virus required for monkey studies in which all control animals must be infected; much lower doses may be required in real practice, given the low sexual transmission frequencies in human populations. A variety of issues must be addressed if the Rao et al (2) approach is to advance to human trials. For one, the requirement for antibiotics to maintain colonization must be eliminated.…”