title: Development of co-selected single nucleotide polymorphisms in the viral promoter precedes the onset of human immunodeficiency virus type 1-associated neurocognitive impairment.
abstract: The long terminal repeat (LTR) regulates gene expression of HIV-1 by interacting with multiple host and viral factors. Cross-sectional studies in the pre-HAART era demonstrated that single nucleotide polymorphisms (SNPs) in peripheral blood-derived LTRs (a C-to-T change at position 3 of C/EBP site I (3T) and at position 5 of Sp site III (5T)) increased in frequency as disease severity increased. Additionally, the 3T variant correlated with HIV-1-associated dementia. LTR sequences derived by longitudinal sampling of peripheral blood from a single patient in the DrexelMed HIV/AIDS Genetic Analysis Cohort resulted in the detection of the 3T and 5T co-selected SNPs before the onset of neurologic impairment, demonstrating that these SNPs may be useful in predicting HIV-associated neurological complications. The relative fitness of the LTRs containing the 3T and/or 5T co-selected SNPs as they evolve in their native patient-derived LTR backbone structure demonstrated a spectrum of basal and Tat-mediated transcriptional activities using the IIIB-derived Tat and colinear Tat derived from the same molecular clone containing the 3T/5T LTR SNP. In silico predictions utilizing colinear envelope sequence suggested that the patient's virus evolved from an X4 to an R5 swarm prior to the development of neurological complications and more advanced HIV disease. These results suggest that the HIV-1 genomic swarm may evolve during the course of disease in response to selective pressures that lead to changes in prevalence of specific polymorphisms in the LTR, env, and/or tat that could predict the onset of neurological disease and result in alterations in viral function.
authors.affiliation: Department of Microbiology and Immunology, Drexel University College of Medicine, 245 N. 15th Street, MS #1013A, Philadelphia, PA 19102, USA.
authors.forename: Luna
authors.initials: L
authors.lastname: Li
authors.forename: Benjamas
authors.initials: B
authors.lastname: Aiamkitsumrit
authors.forename: Vanessa
authors.initials: V
authors.lastname: Pirrone
authors.forename: Michael R
authors.initials: MR
authors.lastname: Nonnemacher
authors.forename: Adam
authors.initials: A
authors.lastname: Wojno
authors.forename: Shendra
authors.initials: S
authors.lastname: Passic
authors.forename: Katherine
authors.initials: K
authors.lastname: Flaig
authors.forename: Evelyn
authors.initials: E
authors.lastname: Kilareski
authors.forename: Brandon
authors.initials: B
authors.lastname: Blakey
authors.forename: Jade
authors.initials: J
authors.lastname: Ku
authors.forename: Nirzari
authors.initials: N
authors.lastname: Parikh
authors.forename: Rushabh
authors.initials: R
authors.lastname: Shah
authors.forename: Julio
authors.initials: J
authors.lastname: Martin-Garcia
authors.forename: Brian
authors.initials: B
authors.lastname: Moldover
authors.forename: Laila
authors.initials: L
authors.lastname: Servance
authors.forename: David
authors.initials: D
authors.lastname: Downie
authors.forename: Sharon
authors.initials: S
authors.lastname: Lewis
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Jacobson
authors.forename: Dennis
authors.initials: D
authors.lastname: Kolson
authors.forename: Brian
authors.initials: B
authors.lastname: Wigdahl
mesh_terms: D015526:AIDS Dementia Complex / Q000821:virology*; D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D002460:Cell Line; D015967:Gene Expression Regulation, Viral; D005838:Genotype; D015658:HIV Infections / Q000821:virology; D016325:HIV Long Terminal Repeat; D015497:HIV-1 / Q000235:genetics* / Q000472:pathogenicity* / Q000502:physiology; D006801:Humans; D008137:Longitudinal Studies; D008875:Middle Aged; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D015533:Transcriptional Activation; D014779:Virus Replication; D054299:env Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism
chemical_list: D054299:env Gene Products, Human Immunodeficiency Virus; D054322:tat Gene Products, Human Immunodeficiency Virus