The antigenic structure of HIV proteins was analyzed semiempirically. Peptides mimicking fragments of the main structural HIV-1 proteins (p17, p24, gp41, and gp120) were selected and synthesized, with account taken of the level of conservation of various HIV genome fragments. The synthesized peptides were then subjected to immunological study with human sera in an enzyme-linked immunosorbent assay (ELISA). Peptides from two regions were found to be particularly immunoreactive with sera from HIV-1 infected persons: the C-terminal end of gp120 and a sequence approximately sixty to eighty amino acids in from the N-terminus of gp41. In fact, more than 96% of HIV-1 positive sera reacted with peptide 495-516 of gp120 (SP-III), peptide 584-602 of gp41 (LS-19), and peptide 601-616 of gp41 (SP-15). Additionally, twelve out of twelve serum samples from Ugandans infected with HIV-1 reacted with both SP-III (from HTLV-III) and SP-29 (gp41, 598-609; from the LAV-ELI isolate), suggesting that these immunodominant sites are useful diagnostically irrespective of the infecting isolates. HIV-2 peptides were also synthesized, and immunoreactivity and cross-reactivity examined. Only two peptides (581-603 of gp32 and 592-605 of gp32) reacted with all of the six HIV-2 positive sera tested. These peptides did not react with HIV-1 positive sera or control sera from healthy blood donors.(ABSTRACT TRUNCATED AT 250 WORDS)