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

Abstract

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/mul to <200 CD4 T cells/mul.

FIG. 1.

Association of candidate and known alleles with HIV-1 cell permissiveness ex vivo. (A) Candidate genes. (B) A selection of previously reported host genetic variants influencing HIV-1 infection. Bars represent median values. Shown are P values estimated by a Kruskal-Wallis test and by a Spearman rank test for trend.

FIG. 2.

Association of candidate and known alleles with HIV-1 disease progression in vivo. (A) Difference in square root CD4 gradient comparing carriers of a rare allele with patients homozygous for the common allele (whiskers show 95% confidence interval). (B) Ex vivo/in vivo correlation for markers associated with differences in permissiveness or disease progression.