Prevalence of resistance-associated viral variants to the HIV-specific broadly neutralising antibody 10-1074 in a UK bNAb-naïve population

Abstract

Broadly neutralising antibodies (bNAbs) targeting HIV show promise for both prevention of infection and treatment. Among these, 10-1074 has shown potential in neutralising a wide range of HIV strains. However, resistant viruses may limit the clinical efficacy of 10-1074. The prevalence of both de novo and emergent 10-1074 resistance will determine its use at a population level both to protect against HIV transmission and as an option for treatment. To help understand this further, we report the prevalence of pre-existing mutations associated with 10-1074 resistance in a bNAb-naive population of 157 individuals presenting to UK HIV centres with primary HIV infection, predominantly B clade, receiving antiretroviral treatment. Single genome analysis of HIV proviral envelope sequences showed that 29% of participants' viruses tested had at least one sequence with 10-1074 resistance-associated mutations. Mutations interfering with the glycan binding site at HIV Env position 332 accounted for 95% of all observed mutations. Subsequent analysis of a larger historic dataset of 2425 B-clade envelope sequences sampled from 1983 to 2019 revealed an increase of these mutations within the population over time. Clinical studies have shown that the presence of pre-existing bNAb mutations may predict diminished therapeutic effectiveness of 10-1074. Therefore, we emphasise the importance of screening for these mutations before initiating 10-1074 therapy, and to consider the implications of pre-existing resistance when designing prevention strategies.

Keywords: 10-1074; HIV - human immunodeficiency virus; broadly neutralising antibodies; primary HIV infection (PHI); resistance screening.

Figure 1

Distribution of predicted 10-1074 resistance in different HIV clades in the HEATHER cohort. (A) ML phylogenetic tree showing all sequences from 157 participants in the HEATHER cohort. The inner ring layer marks sequences with mutations associated with 10-1074 resistance in red and sensitive sequences in green. The outer ring layer shows the sequence clades. (B) Barplot showing the distribution of samples with 10-1074 resistance-conferring mutations per clade. The number in brackets is the number of samples. The percentage of samples in each clade is on the y-axis.

Figure 2

Heatmap presenting the frequency of mutated sites in the HEATHER cohort samples. This heatmap illustrates the frequency of mutations in the protein sequence in individual samples at HXB2 Env positions associated with 10-1074 susceptibility. Each row in the heatmap represents a distinct sample, and the first five columns correspond to precise amino acid positions. The last column illustrates the presence of a PNG at position 334. All samples harbouring >1 sequence with predicted resistance to 10-1074 B clade samples are shown in the upper panel and non-B are shown in the lower. The colour scale shows the percentage of sequences with 10-1074-associated mutations, per sample.

Figure 3

Analysis of Los Alamos Database B clade env sequences. (A) Time series analysis showing the proportion of sequences with 10-1074 resistance-associated mutations in the total number of sequences available per year. The trend line is shown in red, and the confidence intervals are shaded grey. Years for which less than 5 sequences where available were excluded from the analysis. (B) Frequency of individual mutation patterns associated with 10-1074 resistance among all sequences predicted as resistant, sampled throughout the pandemic. The type of mutation is encoded as ‘PNG’, for mutations affecting the 332-glycan binding (332-334 sites), ‘GDIR’ for mutations impacting the binding site on the protein (sites 325 and 330) and ‘Both’ for mutations occurring in both regions in the same sequence. Each mutation pattern is marked with a different colour. The year of sampling is on the x-axis and the proportion of resistant B-clade sequences per year is on the axis. The coloured bands represent the confidence interval for each fitted line.

Figure 4

Forest plots showing the odds ratio of 10-1074 resistance in relation to each of the HIV Env variable loop lengths in the HEATHER cohort. ** indicates a p-value<0.001.

Figure 5

ML phylogenetic trees tracing the evolution of nucleotide sequences in nine participants (A–I) from the HEATHER cohort, amplified with SGA, with ancestral roots annotated with predicted sensitivity. Red points indicate 10-1074 resistant and blue points indicate sensitive sequences. The status of the most recent ancestor is represented as a pie chart at the root of the tree; (A–E) show trees with roots predicted to be sensitive (or most likely sensitive) to 10-1074 and (F–I) show trees with roots predicted to be most likely resistant to 10-1074. Data are for proviral nucleotide sequences and maximum likelihood bootstrap support values exceeding 60% are marked with a *. The scale indicating the number of mutations per site based on the length of branches can be found at the bottom of each tree plot.