Consistent effects of TSG101 genetic variability on multiple outcomes of exposure to human immunodeficiency virus type 1.
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.
Bashirova
Arman A
AA
Laboratory of Genomic Diversity, SAIC-Frederick, Inc., National Cancer Institute, Frederick, Maryland 21702, USA.
Bleiber
Gabriela
G
Qi
Ying
Y
Hutcheson
Holli
H
Yamashita
Traci
T
Johnson
Randall C
RC
Cheng
Jie
J
Alter
Galit
G
Goedert
James J
JJ
Buchbinder
Susan
S
Hoots
Keith
K
Vlahov
David
D
May
Margaret
M
Maldarelli
Frank
F
Jacobson
Lisa
L
O'brien
Stephen J
SJ
Telenti
Amalio
A
Carrington
Mary
M
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
D004268:DNA-Binding Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D014157:Transcription Factors; D000099177:Tsg101 Protein