Inhibition of HIV-1 replication in chronically infected cell lines and peripheral blood mononuclear cells by retrovirus-mediated antitat gene transfer

Li, Y; Starr, S E; Lisziewicz, J; Ho, W-Z
February 2000
Gene Therapy;Feb2000, Vol. 7 Issue 4, p321
Academic Journal
Among potential genetic targets for intervention in the HIV1 life cycle, the tat gene product is a key target. We investigated the ability of an antitat gene to inhibit HIV-1 activation and replication in chronically infected promonocyte (U1) and T cell (ACH-2) lines in vitro. U1 and ACH-2 cells were transduced with an antitat gene expressing RNA with dual (polymeric Tat activation response element and antisensetat) function that interferes with HIV-1 replication. Tumor necrosis factor-alpha (TNF-α) plus phorbol 12-myristate 13acetate (PMA)-induced HIV-1 expression, as determined by reverse transcribed PCR and reverse transcriptase (RT) assays, was significantly inhibited in U1 and ACH-2 cells transduced with the antitat gene, compared with the cells transduced with control vector and untransduced cells. This resistance to TNF-α plus PMA-induced HIV-1 expression was demonstrated in antitat gene-transduced U1 and ACH2 cells maintained in G418-free media for 5 months, suggesting that functional antitat gene may persist for many months in transduced cells and their progeny. Most importantly, we demonstrate that the antitat gene, when introduced into peripheral blood mononuclear cells (PBMC) isolated from patients with HIV-1 infection, inhibited TNF-α plus PMA-induced viral replication as determined by RTPCR and RT activity. In addition, the antitat gene enhanced the survival of CD4[sup +] T lymphocytes from such patients. These data suggest the feasibility of utilizing antitat gene therapy to block activation and replication of HIV-1 in latently infected monocytes and T-lymphocytes in vivo.


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