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Human immunodeficiency virus (HIV) infection among substance abusers is on the rise worldwide. Psychostimulants, and in particular methamphetamine (METH), have detrimental effects on the immune system as well as causing a progressive neurodegeneration, similar to HIV infection. Many Lentivirinae, including feline immunodeficiency virus (FIV), penetrate into the central nervous system early in the course of infection with astrocytes serving as a reservoir of chronic brain infection. We demonstrate that the FIV-Maryland isolate infects feline primary and cell line (G355-5)-cultured astrocytes only under cell-associated conditions. Infected astrocytes yielded a new astrocytotropic isolate, capable of cell-free infection (termed FIV-MD-A). This isolate contained four amino acid substitutions in the envelope polyprotein resulting in a change in net charge as compared to FIV-MD. Infection for both isolates was dependent upon a functional astrocyte CXCR4 receptor. Methamphetamine increased significantly FIV replication in feline astrocytes for cell-associated infection only, with no effect on peripheral blood mononuclear cells or astrocytes infected with FIV-MD-A. This viral replication was related to proviral copy number, suggesting the effect of METH is at the viral entry or integration into host genome levels, but not at the translational level. Thus, lentiviral infection of the brain in the presence of the psychostimulant METH may result in enhanced astrocyte viral replication, producing a more rapid and increased brain viral load. Journal of NeuroVirology (2002) 8, 240-249. [ABSTRACT FROM AUTHOR]