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Journal of Virology, July 2006, p. 6757-6763, Vol. 80, No. 14
0022-538X/06/$08.00+0     doi:10.1128/JVI.00094-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Consistent Effects of TSG101 Genetic Variability on Multiple Outcomes of Exposure to Human Immunodeficiency Virus Type 1{dagger}

Arman A. Bashirova,1,{ddagger} Gabriela Bleiber,2 Ying Qi,3 Holli Hutcheson,1 Traci Yamashita,4 Randall C. Johnson,3 Jie Cheng,3 Galit Alter,5 James J. Goedert,6 Susan Buchbinder,7 Keith Hoots,8 David Vlahov,4 Margaret May,9 Frank Maldarelli,10 Lisa Jacobson,4 Stephen J. O'Brien,1 Amalio Telenti,2 and Mary Carrington3*

Laboratory of Genomic Diversity, National Cancer Institute, Frederick, Maryland 21702,1 Institute of Microbiology and Division of Infectious Diseases, University Hospital of Lausanne, Lausanne, Switzerland,2 Laboratory of Genomic Diversity, SAIC-Frederick, Inc., National Cancer Institute, Frederick, Maryland 21702,3 Department of Epidemiology, School of Hygiene and Public Health, The Johns Hopkins University, Baltimore, Maryland,4 Partners AIDS Research Center, Massachusetts General Hospital, 55 Fruit Street, Charlestown, Massachusetts 02129,5 Viral Epidemiology Branch, Division of Cancer Epidemiology and Genetics, NCI, Bethesda, Maryland,6 University of California, San Francisco, California,7 Gulf States Hemophilia Center, University of Texas Health Science Center, Houston, Texas,8 Department of Social Medicine, University of Bristol, Bristol, United Kingdom,9 HIV Drug Resistance Program, National Cancer Institute, Bethesda, Maryland,10

Received 13 January 2006/ Accepted 16 April 2006

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.

* Corresponding author. Mailing address: Laboratory of Genomic Diversity, SAIC-Frederick, Inc., National Cancer Institute, Frederick, Maryland 21702. Phone: (301) 846-1390. Fax: (301) 846-1909. E-mail: carringt{at}mail.ncifcrf.gov.

{dagger} Present address: Johns Hopkins University School of Medicine, Baltimore, MD 21231.

{ddagger} Supplemental material for this article may be found at http://jvi.asm.org.

Journal of Virology, July 2006, p. 6757-6763, Vol. 80, No. 14
0022-538X/06/$08.00+0     doi:10.1128/JVI.00094-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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