Author:

Abstract:

THE INFLUENCE OF GENETIC VARIATION OF TRANSPORTIN-SR2 (TNPO3) GENE ON SUSCEPTIBILITY TO HIV-1 INFECTION AND DISEASE OUTCOMES Paradise Madlala (1,3), Ping An (4), Frauke Christ (5), Lise Werner (2), Sengeziwe Sibeko (2), Salim S. Abdool Karim (2), Cheryl A. Winkler (4), Zeger Debyser (5), Thumbi Ndung’u (1,2) (1) HIV Pathogenesis Programme, University of KwaZulu-Natal, Durban, South Africa; (2) Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South Africa; (3) Department of Genetics, University of KwaZulu-Natal, Pietermaritzburg, South Africa; (4) Laboratory of Genomic Diversity, Science Applications International Corporation-Frederick, National Cancer Institute-Frederick, Frederick, Maryland, United States of America; (5) Molecular Medicine, Katholieke Universiteit Leuven, B-3000 Leuven, Flanders, Belgium Background. Transportin-SR2 (TRN-SR2), a protein encoded for by the TNPO3 gene has been shown to play an essential role in the HIV-1 replication cycle. However, it is unknown whether genetic variants in the TNPO3 gene alter HIV-1 exposure and infection outcomes. We studied the association between genetic variation in the TNPO3 gene and HIV acquisition and disease progression in two South African based HIV-1 study cohorts. Methods. Eight haplotype tagging SNPs (rs13242262; rs2305325; rs11768572; rs1154330; rs35060568; rs8043; rs6957529; rs10229001) were genotyped in 195 HIV-1 seronegative, 52 primary infected (within one year of infection) and 403 chronically infected black South Africans using TaqMan assays. Results. We found that the minor allele (G) of rs1154330 was significantly associated with increased susceptibility to HIV-1 acquisition (RH 7.13, IC [3.06 – 16.50], p<0.01; Cox model), lower CD4+ T cell counts and higher viral loads during primary infection (p < 0.01; GEE model). Lastly, this G allele of SNP4 was further associated with rapid disease progression as was reflected by higher rate of CD4+ T cell loss (p < 0.01; GEE model) in the chronic infection cohort. Conclusions. In this study we demonstrated that genetic variation A