Receptive anal intercourse (AI) is a common practice among heterosexuals with rates from 5-10% in the general population of women up to 30-50% among women with other risk for HIV infection, both in the US and abroad. AI is considered to be the most common route of HIV transmission in men who have sex with men (MSM). Because of this broad and continuing HIV risk, topical HIV rectal microbicides are being developed to prevent rectal sexual transmission of HIV. The overall MDP proposal addresses the need to define the optimal means of developing rectal microbicides for the prevention of HIV transmission associated with anal intercourse (AI). Assessments of safety and efficacy for rectal microbicides must consider that rectal intercourse itself may induce mucosal inflammation, negatively conditioning the environment in which the microbicides will be tested as well as confounding the safety indices by which a drug candidate would be evaluated. We hypothesize that the mechanical trauma of AI damages the mucosa with subsequent inflammatory changes which both enhance the risk for HIV infection in the seronegative host and increase HIV shedding in the seropositive host. Failure to adjust for these modifiers of safety and efficacy may result in both (i) falsely attributing AI toxicity to the microbicide and (ii) failing to demonstrate efficacy because of simultaneous enhancement of HIV infection due to AI. To characterize the immuno-inflammatory consequences of AI on the rectal mucosa, we propose to simulate AI in clinical studies. In escalating dose-response studies, we will (1) reproducibly expose the rectal mucosa to increasing degrees of coital stress through the use of simulated AI, based on behaviorally relevant conditions. Comparing results from partnered couples in a similarly designed trial will (2) validate the results from the simulated model, and support its use in future studies. To support these studies, we will also (3) define the temporal evolution of the mucosal response to mechanical (AI) and chemical (Nonoxynol-9) trauma and (4) define performance characteristics of novel rectal permeability measurements.