Human genetics of HIV infection

Human Immunodeficiency Virus Type 1 (HIV-1) continues to pose a significant global public health challenge. Marked inter-individual variability in susceptibility to infection, viral load, and disease progression has long highlighted an important role for host genetic factors. To date, only a small number of germline loci show consistent, reproducible effects on HIV-1 control, most notably CCR5 and HLA class I genes. Recent studies have refined the mechanistic basis of these associations, clarifying how CCR5 regulation and specific HLA-B residues shape CD8⁺ T-cell and natural killer cell responses. Beyond these loci, emerging population-specific associations, including variants at the CHD1L/PRKAB2 locus, underscore the importance of studying diverse populations and highlight novel pathways influencing viral replication and evolution. In parallel, attention has shifted toward somatic genetic variation and aging-related processes in people living with HIV-1. HIV-1 infection and chronic immune activation are associated with genomic instability, accelerated accumulation of mitochondrial DNA mutations, telomere shortening, and increased prevalence of clonal hematopoiesis, processes that may contribute to inflammation and non-communicable comorbidities despite effective viral suppression. As well, the growing application of polygenic risk scores to predict cardiometabolic and renal disease in treated populations has implications for precision HIV-1 medicine. As universal antiretroviral therapy reduces opportunities to study natural HIV-1 progression, future genetic research will increasingly focus on how host germline and somatic variation influence therapeutic outcomes and viral reservoir dynamics to shape long-term health outcomes and emerging treatment strategies.