Inhibition of HIV-1 in the Central Nervous System by IFN- α 2 Delivered by an SV40 Vector

Abstract

In human immunodeficiency virus type 1 (HIV-1)-infected individuals, virus-induced production of interferon α (IFN-α) is impaired. In order to obtain regulated expression of IFN-α that responds to HIV-1 infection, a recombinant SV40 vector was designed that carries the human IFN-α2 cDNA under the control of the HIV-1 long terminal repeat (LTR) (SV[HIVLTR]IFN). Thus, the IFN-α2 gene would be trans-activated on infection with HIV-1. This vector was tested to determine if central nervous system (CNS) cell types that may be potential HIV-1 targets could be transduced and protected from HIV. SV[HIVLTR]IFN transduced NT2 cells, a human neuronal precursor cell line, mature neurons derived from NT2 precursor cells, and human primary monocyte-derived macrophages. IFN-α2 expression was retained in mature neurons after SV[HIVLTR]IFN-transduced NT2 precursor cells were induced to differentiate using retinoic acid. IFN-α expression was detected only after exposing transduced cells to HIV. Furthermore, SV[HIVLTR]IFN-delivered IFN-α2 expression significantly inhibited replication of multiple strains of HIV in both NT2 and NT2-derived mature neurons. SV[HIVLTR]IFN transduction also inhibited HIV-1_BaL replication in human primary monocyte-derived macrophages. Therefore, we have demonstrated the effectiveness of IFN-α2, delivered by an SV40 vector driven by HIV-1 LTR as a promoter, to protect several CNS-based, potentially HIV-susceptible cell types. These findings may have implications for therapy of HIV-1 infection in the CNS.