Questions regarding the potential impact of complement-activating antibodies on lentivirus pathogenesis and vaccine development were addressed in the SIV/macaque model by evaluating sera for activity related to complement-mediated, antibody-dependent enhancement (C'-ADE) of SIV infection in vitro. C'-ADE activity in sera obtained during acute primary infection in macaques inoculated with SIVmac251 appeared before neutralizing antibodies and coincided with the initial peak and decline of plasma antigenemia. The power of C'-ADE activity (i.e., virus production measured by p24 immunoassay) decreased as titers of neutralizing antibodies increased in these animals, suggesting a balance in the net effect between C'-ADE and neutralizing activities in vitro. Antibodies with C'-ADE activity were also induced in macaques immunized with live-attenuated SIVmac239/nef-deletion or primed with recombinant SIVmne gp120 vaccinia virus and boosted with SIVmne rgp160. The titer (i.e., last serum dilution to show enhancement), peak (i.e., serum dilution producing the greatest enhancement as measured by p24 production), and power (i.e., magnitude of p24 production at the peak titer) of C'-ADE activity in sera obtained from vaccinated macaques on the day of challenge were comparable to those of sera from infected macaques and showed no correlation with vaccine outcome, where some protected animals had C'-ADE profiles that resembled those of unprotected animals. The results of these studies suggest that antibodies having C'-ADE activity in vitro could contribute to virus replication or, alternatively, to virus clearance during the acute stage of SIV infection in macaques.(ABSTRACT TRUNCATED AT 250 WORDS)