FIG. 1.

(a) Right drug at the right place. The amount of drug available at sites of exposure to HIV (vaginal, rectal, and penile) depends on a suitable delivery system. Drug levels in the female genital tract following oral dosage are significantly lower than what can be achieved using topical delivery systems (depicted by dashed red line). Drugs may act on the virus (virucidals and binding agents), at the cell surface (entry inhibitors), or intracellularly (inhibitors of reverse transcriptase, integrase, and protease) and must be present in sufficient amount at the appropriate site depending on the mode of action. In addition to protecting local immune cells, these drugs must be able to protect target cells recruited into the mucosa in response to inflammatory signals and have the potential to reach cell reservoirs to achieve protection. (b) Reverse transcriptase inhibitor (RTI) kinetics. In the absence of topical sustained delivery, limited local amounts of nucleoside reverse transcriptase inhibitor (NRTI) and nonnucleoside reverse transcriptase inhibitor (NNRTI) drugs may fail to protect both local and recruited target cells. Flux of phosphorylated NRTIs from intracellular to extracellular space is reduced, therefore recruited drug-naive target cells will have limited exposure to drug and remain susceptible to infection. The ability of NNRTIs to be easily transported in and out of cells makes these drugs more available to recruited immune cells, but also subject to being “flushed” out of local cells, for example, in response to higher volumes of genital tract secretions/semen following sex. This could render local cells susceptible. An ideal approach may therefore consist of an NRTI/NNRTI combination that would provide enough drug to be retained in local cells but also be available to recruited cells. Extensive and reduced drug fluxes are represented by full and dashed arrows, respectively.