The humoral immune response to human immunodeficiency virus type 1 (HIVâ1) was studied in 25 AIDS patients with CD4 lymphocyte counts of less than 400/mm3. Humoral immune responses against tissue culture adapted strains of HIVâ1, and two limitedâpassage patient isolates were investigated. Total antiâHIV antibody levels were not significantly different between different individuals. Neutralizing titres against HIVLAI and HIVSF2 were 10â to 100âfold higher than against clinical isolates. The complementâmediated, antibodyâdependent enhancement of HIVâ1 infection titre was high (mean 1:14,000). Antibodyâcomplement mediated cytotoxicity of both HIVLAI and HIVSF2 was ineffective using human complement as a complement source. The antibodyâdependent, cellâmediated cytotoxicity (ADCC) activity varied against the four isolates with tissue cultureâadapted strains being more susceptible than clinical isolates. Finally, an ADCC effector cell function, natural killer or NK activity, was measured for all 25 patients, and NK activity of patients was decreased by nearly 75% compared to uninfected individuals. In summary, beneficial humoral immune responses are low in HIVâ1 infected individuals with CD4 counts of less than 400/mm3 if the in vitro assay system is constructed to best mimic the in vivo situation. These results suggest that the lack of functional antibody responses to HIV may play an important role in viral pathogenesis.