Therapeutic HIV immunisation followed by latency reversal has been suggested as a strategy to achieve a functional cure for HIV. The efficacy of a therapeutic peptide vaccine to improve antiviral immune responses will depend on the presence of potential escape mutations in the target regions. Here we investigate the HIV phylogenetic composition of the four regions targeted by the therapeutic vaccine Vacc-4x in participants in a clinical vaccine trial.
In a clinical trial, 17 participants on suppressive ART were vaccinated with six doses of the therapeutic HIV gag peptide vaccine Vacc-4x (Bionor Pharma) over 12 weeks, then three doses of romidepsin over three weeks followed by an analytical treatment interruption (ATI). Seven participants were selected for sequencing analysis. We performed single-genome/proviral sequencing of a 2.1 kb region spanning the p24-RT region on HIV-1 DNA and cell-associated RNA from peripheral CD4+ T cells from a total of six time points during the trial, as well as plasma HIV-1 RNA from the ATI. We analyzed HLA-specific CTL epitopes in the four regions targeted by Vacc-4x using the Los Alamos epitope and variant databases. CD8+ immune responses were assessed by intracellular cytokine staining and viral inhibition assays.
In five of the seven participants, we identified CTL epitopes, which contained non-silent mutations in 100% of the sequences obtained from all time points analyzed. Only one participant showed signs of vaccine-induced selection in the rebound plasma virus during the ATI. In this participant, a mutation in one CTL epitope was found in 100% of the plasma RNA sequences, compared to 12% of the proviruses. Notably the rebounding virus formed two distinct clusters in the phylogenetic tree and this participant had the highest rebound doubling time of 2.59 days. Overall, the participants with greater plasma HIV-1 RNA genetic diversity at rebound had a shorter time to viral rebound.
We identified CTL epitope changes at baseline, prior to vacc-4x therapy which may affect the potency of this therapeutic vaccine. However, in two participants we identified no mutations of CTL epitopes and they did not show any improved immune responses to vaccination. These findings highlight the challenges of developing immunogenic therapeutic vaccines for HIV Furthermore, we find that the genetic diversity of the virus at rebound relates to the time it takes for virus to rebound.