PACTG P1059

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. PACTG 1059 is a phase I study which will evaluate the safety and tolerance of HIV-1 recombinant vaccines in young adults. Children and young adults with HIV-1infection have been shown to have relative preservation of thymic function with improved ability to respond to new antigens as compared to older adults. Therefore, the age group of 18-24 years is a reasonable population to evaluate safety and to inform future studies for HIV infected children, adolescents and adults. Once safety is established in this group, further studies will be considered to assess safety in other patient populations and immunogenicity can be further evaluated. Ultimately, these candidate vaccines have potential to be useful as prophylactic and therapeutic vaccines. If the results of the present studies support safety of these products in this patient population, further studies to evaluate potential as therapeutic vaccines will be planned in children, adolescents and young adults. Subjects will receive two pairs of matching recombinant HIV-1 vaccines that utilize a modified vaccinia Ankara (MVA) vector and a fowlpox vector (FPV) (Therion Biologics Corp.). Each vector pair contains identical HIV-1 inserts, one consisting of env/gag and the other of modified tat/rev/nef-RT, derived from a vertically transmitted pediatric primary isolate (C58A1, clade B). The HIV-1 sequences utilized by Therion were isolated at the University of Massachusetts Medical Center from a vertically HIV-1-infected infant by PCR amplification of proviral DNA derived from peripheral blood mononuclear cells, and were designated as HIV-1 strain C58A1 (subtype B, primary isolate). The env gene expressed by the vaccines contains the immunodominant portion of gp41. The tat, rev, nef and reverse transcriptase (RT) genes were modified in order to render the proteins non-functional. The mutated tat protein was tested in a transactivation system and was unable to activate the transcription of HIV-1- long terminal repeat (LTR). The nef-RT fusion gene was tested in a colorimetric immunoassay for retroviral RT activity; no enzymatic activity was detected. These genes were inserted into two MVA and two FPV vectors, one of each pair containing env and gag, and the other containing tat, rev, and a nef-RT fusion gene.