CCR5 regulatory variants and novel loci associated with susceptibility to HIV-1 infection in Sub-Saharan African populations

Background: HIV-1 infection remains a major global health challenge, with Sub-Saharan Africa bearing the highest disease burden. Most GWAS of host susceptibility have been conducted in non-African populations. Methods: We conducted the largest GWAS to date of susceptibility to HIV-1 infection in individuals of SSA ancestry, including 3,069 HIV-1 positive cases and 14,291 HIV-1 negative controls from South and East Africa. Fine-mapping and colocalisation with SABR blood eQTLs evaluated functional mechanisms. Results: Three independent loci reached genome-wide significance: rs2040388 and rs2227010 on chromosome 3 (CCR5AS / upstream of CCR5), rs112358207 on chromosome 1 (ESRRG), and rs113298445 on chromosome 8 (INTS9). The chromosome 3 signal colocalised with eQTL variants for CCR5AS expression. Although CCR5Δ32 is absent in African populations, alternative variants in the CCR5 regulatory region may modulate susceptibility. Conclusions: This study revealed both shared and population-specific genetic determinants of HIV-1 susceptibility and underscores the central role of CCR5 regulation in host defence.