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Journal of Virology, October 2005, p. 12674-12680, Vol. 79, No. 20
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.20.12674-12680.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Use of a Combined Ex Vivo/In Vivo Population Approach for Screening of Human Genes Involved in the Human Immunodeficiency Virus Type 1 Life Cycle for Variants Influencing Disease Progression

Gabriela Bleiber,^1, Margaret May,^2, Raquel Martinez,¹ Pascal Meylan,¹ Jürg Ott,³ Jacques S. Beckmann,⁴ Amalio Telenti,^,1* the Swiss HIV Cohort Study

Institute of Microbiology, University of Lausanne, Switzerland,¹ Department of Social Medicine, University of Bristol, United Kingdom,² Laboratory of Statistical Genetics, Rockefeller University, New York, New York,³ Medical Genetics, University Hospital of Lausanne, Switzerland; and the Swiss HIV Cohort Study⁴

Received 2 March 2005/ Accepted 20 July 2005

Humans differ substantially with respect to susceptibility to human immunodeficiency virus type 1 (HIV-1). We evaluated variants of nine host genes participating in the viral life cycle for their role in modulating HIV-1 infection. Alleles were assessed ex vivo for their impact on viral replication in purified CD4 T cells from healthy blood donors (n = 128). Thereafter, candidate alleles were assessed in vivo in a cohort of HIV-1-infected individuals (n = 851) not receiving potent antiretroviral therapy. As a benchmark test, we tested 12 previously reported host genetic variants influencing HIV-1 infection as well as single nucleotide polymorphisms in the nine candidate genes. This led to the proposition of three alleles of PML, TSG101, and PPIA as potentially associated with differences in progression of HIV-1 disease. In a model considering the combined effects of new and previously reported gene variants, we estimated that their effect might be responsible for lengthening or shortening by up to 2.8 years the period from 500 CD4 T cells/µl to <200 CD4 T cells/µl.

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

G.B. and M.M. contributed equally to this work.

A.T. is a member of the Swiss HIV Cohort Study.

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