An HIV-1–infected patient had a rebound in viremia when antiviral therapy was discontinued as part of a vaccine research protocol. Careful studies showed that this patient was infected initially with subtype AE of the virus but then became infected with subtype B. There was no evidence of dual infection, so the data indicate that this is a case of superinfection with a different strain of HIV-1. Natural infection does not necessarily produce cross-clade protection, a finding that may have implications for the development of a vaccine against HIV-1.