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Objective: To determine whether the known sequence differences between African and non-African HIV-1 strains are reflected in the serological response., Design and Methods: We investigated the antibody reactivity of 34 Swedish, 30 Tanzanian and 42 Zimbabwean HIV-1-positive sera to 67 synthetic peptides with sequences from North American and African HIV-1 isolates, mostly derived from regions of gag and env known to be antigenic. Not all sera were tested against all peptides., Results: Differences in frequency of reactivity were noted with peptides covering the entire third variable domain (V3), which is a primary neutralization determinant, and the carboxyl terminus of gp120, in two regions of gp41, and the carboxyl terminus of p24. In env Tanzanian sera reacted preferentially with a V3 peptide from the strain JY1 (Zaire). Gradual substitutions in the central motif in V3 of ELI from GLGQ to GPGR, typical of many non-African strains, led to a gradual increase in reactivity of many Swedish sera, but did not affect Tanzanian and Zimbabwean sera, suggesting that the major epitopes recognized by these African sera are outside GPGR. V3 peptides from the MN and Z3 strains reacted with most sera, but missed 30% of those of Tanzanian origin. In the carboxyl terminus of gp120 both sets of African sera reacted preferentially with peptides from strains JY1 and MAL. Swedish sera reacted strongest with analogues from strains Z321 and HXB2. In gp41, Swedish sera showed a weak preference for reactivity with HXB2-derived peptides in the immunodominant region (amino acids 590-620), and further towards the carboxyl terminus (amino acids 620-665)., Conclusion: The differences in serological reactivity were as great between Zimbabwe and Tanzania as between the two African sets and the Swedish. The geographical differences in the pattern of reactivity with HIV peptides probably depend on both host and viral variation and may be developed into a seroepidemiological tool, useful for optimization of future HIV vaccines.