An anti-HIV microbicide comes alive

Topical microbicides are a broad class of agents designed to block or kill infectious microorganisms directly at the site of transmission. With the AIDS pandemic continuing its unrelenting global march (40 million current infections, 14,000 new infections per day) driven largely by sexual transmission, microbicides have moved steadily toward the front line of preventative strategies. Indeed, many candidate anti-HIV microbicides are currently under development, with several already in clinical trials. 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. This delivery mode would be highly advantageous over others requiring repeated topical application before each act of intercourse; also, the engineered bacteria would be relatively simple and inexpensive to manufacture, transport, and store.

Although the general concept of a live microbicide is not new (as noted by Rao et al.), several aspects of this study are particularly noteworthy. The first is the choice of HIV-1 inhibitor: a 52-aa peptide derived from the C-terminal heptad repeat (HR2) region of gp41, the transmembrane subunit of the HIV-1 envelope glycoprotein (Env). Extensive studies have documented the potent neutralizing activities of various HR2-based peptides (3). They block HIV-1 entry by binding to the N-terminal heptad repeat (HR1) region of the gp41 prehairpin metastable intermediate that forms transiently after interaction of the Env gp120 subunit with target cell receptors (CD4 followed …