Background
Combination approaches using antiretroviral therapy (ART) and immunological interventions such as broadly neutralizing antibodies (bNAbs) are showing a promise in inducing antiretroviral-free HIV control, but the underlying mechanisms are not well understood. This study aimed to investigate the diversity and immune-driven evolution of Env and Gag sequences in rebound viruses from participants who initiated ART during acute infection and subsequently underwent analytical treatment interruption (ATI) after receiving an immunotherapeutic intervention with two bNAbs.
Methods
Virus sequences were analysed from seven of 20 early treated South African women enrolled in an ATI-inclusive clinical trial that assessed two bNAbs (VRC07-523LS and CAP256V2LS) plus vesatolimod (NCT05281510). Full-length HIV-1 env and gag sequences were generated by Sanger sequencing of single genome amplicons (SGA) from plasma collected at transmitter/founder and viral rebound during ATI. Rebound virus was obtained within 18 days of initial viremia, with the exception of one participant from whom virus was obtained 336 days post-rebound. Maximum likelihood phylogenetic trees were constructed in Geneious. Amino acid differences between transmitter/founder and rebound viruses were analysed using Highlighter plots.
Results
A total of 227 full-length env SGA sequences (median 17 transmitter/founder and 16 rebound per participant) and 213 full-length gag SGA sequences (median 16 transmitter/founder and 15 rebound per participant) were generated. Six out of the seven participants were living with HIV subtype-C viruses and one participant with a subtype A/C recombinant virus. With the exception of one participant who was sampled for sequencing 336 days after rebound, Env sequence differences observed between transmitter/founder and rebound viruses were not previously reported to alter bNAb sensitivity. Genetic diversity was limited between transmitter/founder and rebound viruses with few amino acid differences observed overall (median=1.5). Similarly, gag sequences at transmitter/founder and rebound were nearly identical. In particular, experimentally confirmed CTL escape mutations in gag sequences present at detection and rebound timepoints were identical (median 3 per participant), except in one participant who developed one new CTL escape mutation at the rebound timepoint.
Conclusions
Results suggest that viral rebound following ATI was not as a result of emergence of bNAb resistance or CTL escape.