A method for the rational design and preparation of vaccines based on HIV envelope polypeptides is described. In one embodiment, the method for making an HIV gp120 subunit vaccine for a geographic region comprises determining neutralizing epitopes in the V2 and/or C4 domains of gp120 of HIV isolates from the geographic region and selecting an HIV strain having gp120 a neutralizing epitope in the V2 or C4 domain which is common among isolates in the geographic region. In a preferred embodiment of the method, neutralizing epitopes for the V2, V3, and C4 domains of gp120 are determined. At least two HIV isolates having different neutralizing epitopes in the V2, V3, or C4 domain are selected and used.to make the vaccine. The invention also provides a multivalent HIV gp120 subunit vaccine. A DNA sequence encoding gp120 from preferred vaccine strains of HIV, GNE8 and GNE16, expression constructs comprising the GNE8-gp120 and GNE16-gp120 encoding DNA under the transcriptional and translational control of a heterologous promoter, and isolated GNE8-gp120 and GNE16-gp120 are also described.