title: Consistent effects of TSG101 genetic variability on multiple outcomes of exposure to human immunodeficiency virus type 1.
abstract: Tumor susceptibility gene 101 (TSG101) encodes a host cellular protein that is appropriated by human immunodeficiency virus type 1 (HIV-1) in the budding process of viral particles from infected cells. Variation in the coding or noncoding regions of the gene could potentially affect the degree of TSG101-mediated release of viral particles. While the coding regions of the gene were found to lack nonsynonymous variants, two polymorphic sites in the TSG101 5' area were identified that were associated with the rate of AIDS progression among Caucasians. These single-nucleotide polymorphisms (SNPs), located at positions -183 and +181 relative to the translation start, specify three haplotypes termed A, B, and C, which occur at frequencies of 67%, 21%, and 12%, respectively. Haplotype C is associated with relatively rapid AIDS progression, while haplotype B is associated with slower disease progression. Both effects were dominant over the intermediate haplotype A. The haplotypes also demonstrated parallel effects on the rate of CD4 T-cell depletion and viral load increase over time, as well as a possible influence on HIV-1 infection. The data raise the hypothesis that noncoding variation in TSG101 affects the efficiency of TSG101-mediated release of viral particles from infected cells, thereby altering levels of plasma viral load and subsequent disease progression.
authors.affiliation: Laboratory of Genomic Diversity, SAIC-Frederick, Inc., National Cancer Institute, Frederick, Maryland 21702, USA.
authors.forename: Arman A
authors.initials: AA
authors.lastname: Bashirova
authors.forename: Gabriela
authors.initials: G
authors.lastname: Bleiber
authors.forename: Ying
authors.initials: Y
authors.lastname: Qi
authors.forename: Holli
authors.initials: H
authors.lastname: Hutcheson
authors.forename: Traci
authors.initials: T
authors.lastname: Yamashita
authors.forename: Randall C
authors.initials: RC
authors.lastname: Johnson
authors.forename: Jie
authors.initials: J
authors.lastname: Cheng
authors.forename: Galit
authors.initials: G
authors.lastname: Alter
authors.forename: James J
authors.initials: JJ
authors.lastname: Goedert
authors.forename: Susan
authors.initials: S
authors.lastname: Buchbinder
authors.forename: Keith
authors.initials: K
authors.lastname: Hoots
authors.forename: David
authors.initials: D
authors.lastname: Vlahov
authors.forename: Margaret
authors.initials: M
authors.lastname: May
authors.forename: Frank
authors.initials: F
authors.lastname: Maldarelli
authors.forename: Lisa
authors.initials: L
authors.lastname: Jacobson
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: O'brien
authors.forename: Amalio
authors.initials: A
authors.lastname: Telenti
authors.forename: Mary
authors.initials: M
authors.lastname: Carrington
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000097:blood / Q000235:genetics*; D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000235:genetics*; D018450:Disease Progression; D056827:Endosomal Sorting Complexes Required for Transport; D005260:Female; D005787:Gene Frequency / Q000235:genetics*; D015497:HIV-1; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D016366:Open Reading Frames / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics*; D019562:Viral Load; D017201:Virus Shedding / Q000235:genetics; D000099177:Tsg101 Protein
chemical_list: D004268:DNA-Binding Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D014157:Transcription Factors; D000099177:Tsg101 Protein