Simon Mallal

Mutations in human immunodeficiency virus type 1 (HIV-1) enable the virus to evade recognition and killing by HLA-restricted T cells. These viral adaptations are specific to the HLA type of individuals and are therefore evident as HLA allele-HIV sequence associations at the population level. Most studies of HLA associations have been cross-sectional and may not capture selective changes that have accumulated to reach fixation at the population level, with potential impacts on viral replication and clinical outcomes. In this study, we examined the population from Western Australia to determine if ongoing evolution has occurred over more than 30 years of observation. In addition, we utilised HIV-1 subtype B viral load records (one measurement per individual) from a five-year period early in the epidemic (1997–2002) compared with recent years (2017–2022) to determine whether any population level HIV-1 adaptation has functional impact. Results showed that 120 amino acid positions across the Gag, Pol and Nef genes showed significant change in proportion over time. Of these positions, 35% included one or more amino acids reported as HLA-associated viral adaptations or putative compensatory adaptations. Over two thirds of these adaptations increased in proportion over time, with eight becoming the consensus sequence. We also observed the accumulation of specific compensatory mutations within epitopes presented by protective HLA alleles. There was a significant increase in baseline viral load between the two time periods examined (p < 0.001, OR = 2.4). These findings provide evidence of ongoing HIV-1 adaptation to human immune responses at the population level, with a likely increase in virulence, as captured by viral load. The enrichment of viral adaptations within circulating strains may lead to loss of immune targets for prevalent immune responses and has important implications for vaccine development and cure strategies.