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To determine whether oral sexual exposure to HIV-1 (HIV) results in HIV-neutralizing activity in saliva of uninfected men who have sex with infected men?Saliva samples were collected from HIV IgG seronegative men (n = 25) whose male partners were HIV infected and from low-risk healthy controls (n = 22) and analyzed for HIV-neutralizing capacity.The presence of neutralizing activity in saliva was tested in a peripheral blood mononuclear cell-based assay using primary HIV isolates. Self-reporting questionnaires described the individuals' sexual behaviors and routes of possible HIV exposure.Of 25 exposed, uninfected individuals (EUI), 21 reported receptive unprotected oral intercourse, whereas three of the 25 reported unprotected anal receptive intercourse. Whole saliva from both EUI and low-risk healthy controls contained HIV-neutralizing activity. However, a significant difference was seen when analyzing the salivary IgA1 fraction: 13 of 25 EUI neutralized HIV, whereas none of the 22 controls had this capacity. The neutralizing capacity of the EUI males persisted during 2 years of follow-up.Unprotected oral sex evokes a salivary IgA1-mediated HIV-neutralizing response that persists over time during continuous exposure in uninfected male partners of infected men.