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Susceptibility to HIV infection and disease progression are complex traits modulated by environmental and genetic factors, affecting innate and adaptive immune responses, among other cellular processes. A single nucleotide polymorphism (SNP) 35. kb upstream of the HLA-C gene locus (-35C/T) was previously shown to correlate with increased HLA-C expression and improved control of HIV-1. Here, we genotyped the -35C/T SNP in 639 subjects (180 uninfected patients, 304 HIV progressors and 155 LTNP) and confirmed the association of the -35C/T variant with the LTNP phenotype. The genotype frequencies in the general population subjects did not differ significantly from those seen in HIV progressors (p-value = 0.472). However, a significant higher frequency of the protective CC genotype was identified when LTNP were compared either with HIV progressors alone (p-value < 0.0001) or progressors and uninfected subjects together (p-value < 0.0001). When considering aviremic LTNP alone (elite controllers; viral load below 50. copies/ml), the -35 CC genotype was not overrepresented compared to HIV progressors. Conversely, a significant association was found with the viremic LTNP groups (viral loads below 10,000. copies/ml). These results suggest that other factors alone or in combination with the -35 CC genotype may play an important role in differentiating the elite controller status from LTNP. Combination of different genetic variants may have additive or epistatic effects determining the HIV course of infection. © 2012 Elsevier GmbH., Ministerio de Ciencia e Innovación (BFU2009-06958, SAF2010-18917, RD06/0006/0033); FIPSE 360783-09 and FIPSE 360737-09 projects; the Gala contra la SIDA 2011; Bill and Melinda Gates Foundation (CEvac); Fondo de Investigación Sanitaria (FIS)