Inhibition of HIV-1 in the central nervous system by IFN-alpha2 delivered by an SV40 vector.
In human immunodeficiency virus type 1 (HIV-1)-infected individuals, virus-induced production of interferon alpha (IFN-alpha) is impaired. In order to obtain regulated expression of IFN-alpha that responds to HIV-1 infection, a recombinant SV40 vector was designed that carries the human IFN-alpha2 cDNA under the control of the HIV-1 long terminal repeat (LTR) (SV[HIVLTR]IFN). Thus, the IFN-alpha2 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-alpha2 expression was retained in mature neurons after SV[HIVLTR]IFN-transduced NT2 precursor cells were induced to differentiate using retinoic acid. IFN-alpha expression was detected only after exposing transduced cells to HIV. Furthermore, SV[HIVLTR]IFN-delivered IFN-alpha2 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-alpha2, 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.
Cordelier
Pierre
P
Department of Pathology, Anatomy and Cell Biology, Jefferson Medical College, Philadelphia, PA 19107, USA.
Calarota
Sandra A
SA
Pomerantz
Roger J
RJ
Xiaoshan
Jiang
J
Strayer
David S
DS
D002493:Central Nervous System Diseases / Q000628:therapy; D015316:Genetic Therapy; D005822:Genetic Vectors; D015658:HIV Infections / Q000628:therapy*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007370:Interferon Type I / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins; D013539:Simian virus 40
D007370:Interferon Type I; D011994:Recombinant Proteins