Evidence for circulation of high-virulence HIV-1 subtype B variants in the United Kingdom

The evolution of HIV-1 virulence has significant implications for epidemic control. Recent phylogenomic analyses identified low-prevalence HIV-1 variants exhibiting significant differences in disease progression. We analysed 40 888 partial HIV-1 pol sequences from the UK HIV Drug Resistance Database (UKRDB) across subtypes B, C, A1, and CRF02AG. We identified phylotypes with putative differences in transmission/phylogenetic patterns and assessed their virulence trends using pretreatment viral loads, CD4 cell counts, and four statistical methods. We classified three subtype B phylotypes-PT.B.40.UK, PT.B.69.UK, and PT.B.133.UK -as variants of interest (VOIs) due to significantly higher viral loads and/or accelerated CD4 decline. PT.B.40.UK and PT.B.69.UK exhibited higher viral loads, 4.93 log₁₀ copies/ml (95% CI: 4.73-5.13) and 4.87 (4.65-5.10), representing 0.30-0.36 log₁₀ copies/ml higher than the reference group (4.57; 4.55-4.59). Despite uncertainties in baseline CD4 counts, all three VOIs reached the clinically relevant threshold of 350 CD4 cells/mm³ significantly faster than the reference group (3.5 years, 3.1-3.9 years): 2.3 years (1.0-5.1) for PT.B.40.UK, 2.0 years (10.8 months-4.4 years) for PT.B.69.UK, and 1.8 years (10.8 months-3.6 years) for PT.B.133.UK. These VOIs and their closest relatives have been circulating in the UK for decades with limited international spread and did not exhibit unusually rapid growth rates. Although these findings suggest a heritable high-virulence HIV-1 phenotype, we did not find evidence that convergent genetic polymorphisms or switches in coreceptor usage explained these differences. The small fraction of HIV-1 subtype B variants in the UK evolving towards higher virulence is unlikely to pose a public health concern, given the ongoing decline in new HIV diagnoses following the widespread adoption of pre-exposure prophylaxis and targeted prevention campaigns. However, this study-alongside the detection of the VB variant in the Netherlands-demonstrates that more virulent variants are not rare and can emerge independently in multiple countries. Consequently, HIV-1 genomic surveillance remains crucial to monitor HIV-1 virulence and mitigate its healthcare impact.