The impact of accumulating immune adaptation in circulating strains of HIV-1

Mutations in human immunodeficiency virus type 1 (HIV-1) enable the virus to evade recognition and killing by human leucocyte antigen (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, where HLA-HIV-1 associations were first demonstrated, to determine if ongoing evolution has occurred over more than 30 years of observation.

Cross-sectional HIV-1 subtype B sequences sampled at two time points, early in the epidemic (1992 - 2002, n = 182) and recently (2017 - 2022, n = 119) was utilised to examine HIV-1 evolutionary dynamics overtime. In addition, HIV-1 subtype B viral load records (one measurement per individual) from a five-year period early in the epidemic (1997 - 2002, n = 673) were compared with recent data (2017 - 2022, n = 363) to determine whether any population level HIV-1 adaptation has functional impact.

The analysis identified 120 amino acid positions across the Gag, Pol and Nef genes that showed significant change in proportion over time, with most (100/120; 83.3%) showing an increase in the proportion of one or more of the non-consensus amino acids. Of these positions, 35% (42/120) included one or more amino acids (48; 34 in Pol, 9 in Gag and 5 in Nef) reported as HLA-associated viral adaptations (35/48; 72.9%) or putative compensatory adaptations (11/48, 22.9%). Over two thirds of these adaptations (68.8%; 33/48) increased in proportion over time (range 5.8% to 46%), with eight becoming the consensus sequence. We also observed the accumulation of specific compensatory mutations within epitopes presented by protective HLA alleles. Other accumulated non-consensus amino acid changes (38/120) were predicted to weaken the peptide-HLA binding affinity of known HIV T cell epitopes, suggesting that the previously published list of HLA-associated viral adaptations used in our study was not exhaustive. Only two Pol reverse transcriptase non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance mutations showed a significant change in proportion over time (K256Q [K101Q in reverse transcriptase region]; 22.9%, P-adjusted <0.001 and K258N [K103N in reverse transcriptase region]; 7.7%, P-adjusted = 0.020). Notably, we highlight the significant accumulation of adaptations (Gag: R76K, 40.8%, P-adjusted <0.001; H219Q, 25.8%, P-adjusted = 0.020 and R286K, 24.4%, P-adjusted = 0.036) that confer adaptation to both HLA-restricted T cell immune responses and antiretroviral therapy. 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.