As more HIV-1 infected patients receive anti-retroviral drug treatment, the occurrence of drug-resistant variants of the virus is increasing. We have previously shown that mutated HIV peptide sequences represent mutations induced by antiretroviral drugs are equally good and often better immunogens than wild type peptides. The non-toxic B subunit of cholera toxin (CTB) is an active substance in the oral cholera vaccine, and has been shown to bind ganglioside receptors and activate mucosal cells. By fusing mutant epitopes deriving from HIV-1 enzymes with the B subunit of cholera toxin, we aim is to induce cellular responses against virus harboring drug-induced mutations. We successfully created conjugates of HIV peptide sequences fused to rCTB. The immune response against the different peptides was strongly enhanced by the fusion to the toxin. Moreover, immunization with sequence containing drug-induced mutation triggered a cross-reactive immune response against the wild type epitope. Long-term follow-up of immunized animals revealed a persistence of cellular immune response for over 4 months, which could readily be boosted with an additional late immunization. By linking HIV-peptides to the B subunit of cholera toxin it is thus possible to stimulate a strong and long-lasting immune response, significantly better than that evoked by the peptide alone.