RevM10-Mediated Inhibition of HIV-1 Replication in Chronically Infected T Cells

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Abstract
Two clinical regimens have been proposed for gene therapies of acquired immunodeficiency syndrome (AIDS): (i) Genetic modification of differentiated peripheral mononuclear cells ex vivo and (ii) gene delivery into hematopoietic stem/progenitor cells ex vivo. Various antiviral strategies targeted at different molecular processes in the human immunodeficiency virus type 1 (HIV-1) life cycle are currently being pursued, all with the goal of reducing HIV-1 replication. Until now, all successful studies have reported inhibition in acutely HIV-infected cells that had been genetically modified prior to infection. These promising results do not address a clinically relevant question: What is the contribution of already infected peripheral mononuclear and hematopoietic stem/progenitor cells to disease progression? In this report, we demonstrate inhibition of both HIV-1 replication and production of infectious particles in chronically infected human T leukemia cell lines. The antiviral effect on the transduced cell population correlates with the expression of the dominant-negative RevM10 protein. This is the first demonstration that a gene therapy-based treatment can achieve antiviral efficacy in human T leukemia cells chronically infected with HIV-1. Multiple gene therapy strategies for AIDS have been designed and are currently tested in preclinical in vitro model systems. Until now, all reported studies have tested antiviral activity in cells already genetically modified. The promising results of these initial studies have already led to the NIH-RAC and FDA approval of a phase I clinical study in peripheral blood lymphocytes (Nabel et al., 1994). However, HIV-1 infection is already established in AIDS patients. We tested whether expression of a trans-dominant Rev protein (RevM10) can suppress replication in chronically infected cells. In this report, we demonstrate the first preclinical evidence that RevM10 expression can suppress HIV-1 replication in chronically infected cells in vitro.