Signature sequences within the HIV-1 LTR predictive of HIVD

B Irish; M Nonnemacher; A Alexaki; Yujie Liu; A Banerjee; B Wigdahl

Human immunodeficiency virus type 1 (HIV-1) proviral DNA with specific binding site sequence variants within the long terminal repeat (LTR), that arise during the course of infection, could represent conditionally functional viral promoter sequences, and may be predictive of progressive neurological disease associated with HIV-1 neuroinvasion. The LTR regulates HIV-1 viral gene expression via its interaction with multiple cell and viral factors, including members of the CCAAT/enhancer binding protein (C/EBP) and Sp transcription factor families. We have examined sequence variation within C/EBP sites I and II, and Sp sites I, II, and III in peripheral blood (PB)-derived LTRs from HIV-1-infected patients representing increasing degrees of disease severity. The 3T configuration of C/EBP site I (C-to-T change at nucleotide position 3) and 5T configuration of Sp site III (C-to-T change at nucleotide position 5) were the only variants examined that were found in low frequencies in PB-derived LTRs derived from patients at early stages of HIV-1 disease, and at relatively high frequencies in patients in late stage disease. Sequence variation within these sites was also examined in LTRs derived from various brain compartments of patients with and without HIVD. The 3T C/EBP site I variant was identified in 25% of brain-derived LTRs from patients diagnosed with HIVD, but was absent in patients not suffering from dementia. These results suggest that 3T C/EBP site I, and possibly 5T Sp site III may prove valuable in assessing the likelihood of HIV-1-infected individuals developing HIVD.

Signature sequences within the HIV-1 LTR predictive of HIVD

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Signature sequences within the HIV-1 LTR predictive of HIVD

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Abstract

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