Frequency Variation Among Sub-Saharan Populations in Virus Restriction Gene, BST-2 Proximal Promoter Polymorphisms: Implications for HIV-1 Prevalence Differences Among African Countries Michelle M. Skelton, 1 Elizabeth E. Kampira, 1 Ambroise A. Wonkam, 1 Kudakwashe K. Mhandire, 1 Johnstone J. Kumwenda, 2 Kerina K. Duri, 3 and Collet C. Dandara 1 Abstract The present study reports promoter variants in four sub-Saharan African populations that may affect BST-2 gene regulation. Recently, an in/del within the BST-2 promoter has been associated with HIV-1 disease progression in a Spanish cohort. Hence, we sequenced the proximal promoter region of the BST-2 gene in 581 individuals from South Africa, Zimbabwe, Malawi, and Cameroon. Seven SNPs were identified: rs28413176 (+26i6/D6); rs28413175 (-160i1/D1), -187A > G (nucleotide position -17516614); rs28413174 (-193G > A); rs73921425 (-199G > A); rs12609479 (-201C > T); and rs112492472 (-225C > T). The -199A and -225T alleles showed interesting trends across the sub-Saharan continent. Using predictive bioinformatics tools, we show that allelic variation at -199 and -201 potentially affect key transcription factor binding sites including bHLH, c-Myb, and E47. Importantly, data available from the ENCODE study gave further credence to our hypothesis of tran- scriptional regulation of BST-2 by a bHLH TF such as Mxi1. The possible repressive transcriptional effect of Mxi1 combined with the allelic frequency trend seen at -199 between African populations overlays well with current HIV-1 prevalence data, and may be a contributing factor to this phenomenon. The differences in HIV-1 prevalence in African countries could be, in part, due to distribution of genetic variants that affect susceptibility to HIV-1. Our findings therefore have substantive value for the design of future diagnostics for global health oriented diagnostics for HIV-1 susceptibility, and rational therapeutics on the critical path to personalized medicine in the African continent. As HIV-1 epidemiology vastly impacts human populations around the world, the population genomics strategy we have utilized herein can have value for other global regions as well. Introduction T he broad spectrum antiviral agent, bone marrow stromal cell antigen 2 (BST-2), has been shown to re- strict an ever growing list of lipid-enveloped viruses, which includes retroviruses, filoviruses, herpesviruses, and arena- viruses (Arnaud et al., 2010; Jouvenet et al., 2009; Mansouri et al., 2009; Sakuma et al., 2009; Weidner et al., 2010), the newest additions being flavivirus (hepatitis C and dengue) (Pan et al., 2012, 2013) and paramyxovirus (sendai and nipah) (Kong et al., 2012). The BST-2 gene is located on chromosome 19 (Ishikawa et al., 1995) and is also known as HM1.24, CD317 or tetherin. With respect to HIV-1, BST-2 ‘‘tethers’’ budding virions on the cell surface (Neil et al., 2008), interfering with their dissemination. BST-2 is asso- ciated with reduced infectivity of the newly formed virions (Zhang and Liang, 2010). HIV-1 counters this antiviral action by downregulating BST-2 on the cell surface membrane via Vpu assisted sequestration and subsequent degradation. BST-2 is a type II membrane protein and its unconventional topology allows a dual association with the cell and the virion lipid bilayer during virion assembly. BST-2 consists of a short amino-terminal cytoplasmic tail, followed by an alpha- helical transmembrane domain, a coiled-coiled extracellular domain, and a carboxy terminal glycosylphosphotidylinositol (GPI) modification. The GPI anchors BST-2 within lipid 1 Division of Human Genetics, Faculty of Health Sciences, University of Cape Town, Observatory, Cape Town, South Africa. 2 Department of Medicine, College of Medicine, University of Malawi, Blantyre, Malawi. 3 Department of Immunology, University of Zimbabwe, and Letten Foundation Research House, Harare, Zimbabwe. OMICS A Journal of Integrative Biology Volume 18, Number 7, 2014 ª Mary Ann Liebert, Inc. DOI: 10.1089/omi.2013.0127 461