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Molecular therapeutic approaches to HIV-1 infection and AIDS.
Lisziewicz J; Sun D; Lori F; Peng B; Ensoli B; Agrawal S; Gallo RC;
December 30, 1994
Int Conf AIDS. 1994 Aug 7-12;10(2):118 (abstract no. PA0354). Unique

We have developed an autoregulated, dual function inhibitory gene, anti-Tat, which is expressed only in the presence of HIV-1 Tat. Anti-Tat blocks the function of intra- and extracellular Tat through expression of polymeric-TAR and antisense-Tat RNA. The anti-tat gene, transferred by retrovirus vectors, blocked the spread of HIV-1 in the T-lymphocytic cell line, and the extent and duration were dependent upon viral infectious dose. Virus replication was inhibited up to 7 months in two different cell lines after high multiplicity of infection, suggesting that the anti-tat gene is an effective long-term suppressor. In primary lymphocytes anti-tat gene transfer resulted in up to 4000-fold inhibition of a primary HIV-1 isolate and inhibition of the cytopathic effect of the virus, suggesting a potential use for anti-tat gene therapy to treat HIV-1 infection. Our other approach is the development of GEM91, a 25 nucleotides long antisense oligonucleotide phosphorothioate complementary to Gag mRNA. This compound inhibited HIV-1 replication in a dose-dependent and sequence specific manner in the T-lymphocytic cell line. GEM91 also completely blocked the growth of four different HIV-1 isolates in primary lymphocytes/macrophages. A clinical trial was initiated for the treatment of AIDS based on the antiviral activity, safety and pharmacokinetic profile of GEM91.

Acquired Immunodeficiency Syndrome/*THERAPY Antiviral Agents/THERAPEUTIC USE Cell Line Cells, Cultured Cytopathogenic Effect, Viral/GENETICS Gene Therapy/*METHODS Gene Transfer Genes, gag Genes, tat Human HIV Infections/*THERAPY *HIV-1/GENETICS/PHYSIOLOGY In Vitro Macrophages/MICROBIOLOGY Oligonucleotides, Antisense/GENETICS/THERAPEUTIC USE RNA, Antisense/GENETICS/THERAPEUTIC USE T-Lymphocytes/MICROBIOLOGY Thionucleotides/GENETICS/THERAPEUTIC USE Virus Replication/GENETICS CLINICAL TRIAL ABSTRACT