1. Washington D.C., USA, 22-27 July 2012www.aids2012.org Ping An, James J. Goedert, Sharyne Donfield, Susan Buchbinder, Gregory D. Kirk, Roger Detels and Cheryl A. Winkler ZNRD1 –Zinc Ribbon Domain-Containing 1 –RNA polymerase Genome-wide association study (GWAS) –#1 gene associated with CD4 + T-cell depletion (Fellay et al, 2007). Genome-wide gene knock-down –One of 250 host proteins required by HIV- 1 (Brass et al, 2008). Affects host susceptibility to HIV-1 infection? HIV-1 infection susceptibilityHIV-1 infection susceptibility –SNP frequencies Exposed uninfected vs. HIV-1 infected HIV-1 natural history cohortsHIV-1 natural history cohorts –1865 European Americans MACS, SFCC, MHCS, HGDS –837 African Americans ALIVE 13 SNPs, ZNRD1-RNF39-HLA-C13 SNPs, ZNRD1-RNF39-HLA-C Abstract no. MOPDA0104 ZNRD1 gene affects host susceptibility to HIV-1 infection BackgroundMethods

2. Washington D.C., USA, 22-27 July 2012www.aids2012.org ZNRD1 haplotype Hap2 on risk of HIV-1 acquisition ZNRD1 Haplotypes Haplotype SNP1-12 Frequency in EA Hap1 TTGGGGGATGTA 0.66 Hap2 TTGGCGAATGTA 0.12 Hap3 TTGGGGGAGGTA 0.09 Hap4 GCAAGAGGTTGG 0.06 Hap5 GCAAGGGGTTGG 0.04 Impact on HIV-1 infection Hap2 carrier frequency: HIV - (29%) vs. HIV + (21%) OR for infection = 0.65, P = 0.005  High-risk exposed uninfected (HREU) vs. HIV-1 seroconverters (P = 0.04)  In Africa America, OR=0.67, P=0.23  HLA-C rs9264942 (P = 0.40) Hap2 tag SNP rs3132130 (-1850) Cell-specific binding to transcription factors The sequence carrying rs3132130 C  G SNP differentially binds to nuclear factors in a gel-shift assay. (A) Serum response HeLa cells, (B) PMA HeLa cells, C) PHA Jurkat T cells. Results

3. Washington D.C., USA, 22-27 July 2012www.aids2012.org Kaplan–Meier survival curves of HIV-1 progression from seroconversion to CD4<200, stratified by ZNRD1 rs8321 genotypes in European Americans HIV-1 disease progression Hap3  1 year faster to CD4 <200  Cox model: RH = 1.39  Tagged by 3’UTR rs8321 Conclusions The first epidemiologic evidence that ZNRD1 mediates host resistance/susceptibility to HIV-1 infection Authors declare no conflicts of interest Funded by National Cancer Institute HHSN26120080001E Results