Beyond CCR5 and HLA: rare genetic variants in HIV acquisition and disease progression

The CCR5 locus and the HLA class I region, first identified through candidate gene studies, remain the most well-characterized host genetic factors associated with HIV acquisition and disease progression, respectively. To date, genome wide association studies (GWAS) including those with several thousand individuals have largely replicated these same loci with very few additional associations identified. Increasingly, rare variants with larger effect sizes have been proposed to contribute to the unexplained inter-individual variability in HIV acquisition and disease progression. In this review, we highlight findings from rare variant studies across different populations and discuss the phenotypic and analytical challenges that impede discovery. We further highlight African ancestry cohorts as a valuable resource for rare variant discovery, given Africa's extensive genetic diversity and disproportionate HIV burden. We emphasize the use of historical cohorts of persistently exposed but uninfected individuals as well as ART naïve HIV infected individuals, as these are increasingly difficult to recruit prospectively. Rare variant studies have the potential to reveal genes essential for HIV susceptibility and disease progression highlighting targets for novel HIV vaccines and therapeutics.