HIV-1 LTR DNA sequence variation in brain-derived isolates.

Isolates of human immunodeficiency virus (HIV-1) derived from the central nervous system (CNS) display properties distinctive from blood-derived isolates, including a high incidence of macrophage tropism in CNS isolates. Macrophage tropism is a result, in part, of DNA sequence variation in the HIV-1 envelope glycoprotein gene, but evidence also exists suggesting differences in the long terminal repeat (LTR) may contribute to differential gene expression. To investigate the nature of HIV-1 LTR sequence variation in the brain, we have sequenced bases -374 to +43 of the LTR from the brains of four HIV-1-infected patients. A total of 56 clones were derived from either both gray and white matter (three brains) or white matter alone (one brain), and these sequences were compared to 17 published sequences derived from multiple sources. A total of five LTR quasispecies were found. Overall, there was a significant amount of sequence variation both within and between brains, comparable to that seen in quasispecies of the envelope glycoprotein derived from blood or brain. The vast majority of the variation was seen in regions upstream from the two NF-kappa B sites. Compared to the blood-derived, T cell-tropic IIIB LTR, a majority of clones from two or more of the brains shared 11 unique substitutions in transcription factor binding sites, of which eight were shared with the CNS-derived clones JR-CSF and JR-FL and altered the NF-AT and LEF-1 transcription factor binding sites. These findings correlate with published functional studies showing CNS-derived HIV-1 LTRs are distinct from the blood-derived IIIB LTR, and represent a starting point for future studies designed to determine which LTR sequence variations are associated with cell-specific differences in gene expression in the CNS.