As outlined above, despite recent and past immunization studies demonstrating that HTLV-I envelope proteins can induce protective responses, no effort has been made to determine if other HTLV-I proteins, particularly the gag proteins, can also elicit a protective immune response. Mapping the HTLV-I gag region for immunogenic B-cell epitopes through the use of human-infected sera has identified several B-cell epitopes especially in p19.162 This information has resulted in the development of diagnostic tests for HTLV-I, but has not lead to any synthetic gagpeptide approaches being tested in animal models. There also has not been any attempt to identify T-helper or cytotoxic epitopes within any of the gag proteins. There have been studies ofHTLV-I-infected rats describing anti-gag T-cell responses.8687 Another study demonstrated that incorporation of a gag- envelope fusion protein into a mannan-coated liposome is able to prime predominantly gag, but also envelope cytotoxic T-cell responses.163 Whether any of these cyto-toxic T-lymphocyte (CTL) responses could prevent HTLV-I infection remains unclear because none of the animals were challenged with HTLV-I.

The development of recombinant viral, DNA, and gag- protein immunization strategies is hampered by apparent cisacting negative regulatory sequences present in the gag region of HTLV-I that possibly require the presence of Rex to Overcome.164 Similar sequences have been described for HIV-1.165 Though recombinant adenoviruses containing the HTLV-I gag-protease region have been constructed, these recombinant adenoviruses failed to generate detectable levels of gag protein in infected cultured cells and were unable to induce anti- gag antibody responses in mice (G. A. Dekaban and F. Graham, unpublished data). Recombinant poxviruses, on the other hand, are able to effectively express the HTLV-I gag and env proteins due to the cytoplasmic nature of poxvirus replication. These viruses are currently being used in rat, rabbit, and baboon immunogenicity studies (G. A. Dekaban, J. Allen, J. Tartaglia, and G. Franchini, unpublished data). In addition, DNA immunization vectors have been successfully constructed to express the HTLV-I p24; however, no expression of p19 has yet been observed (G. A. Dekaban, unpublished data). Lack of successful p19 expression suggests that the cis- acting negative regulatory sequences may be present in the p19 region of the gag gene; however, further experimentation, currently underway, is required to resolve this issue. Thus, if adenovirus or DNA immunization vectors are to be used as vaccines capable of expressing HTLV-I gag proteins, Rex will have to be coexpressed. Alternatively, the exact location of the cis- acting negative regulatory sequences will have to be identified and mutated or eliminated to permit expression of the gag proteins from the precursor protein or expression of p19 by itself.

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