CD8 and CD4 epitope predictions in RV144: no strong evidence of a T-cell driven sieve effect in HIV-1 breakthrough sequences from trial participants

Abstract

The modest protection afforded by the RV144 vaccine offers an opportunity to evaluate its mechanisms of protection. Differences between HIV-1 breakthrough viruses from vaccine and placebo recipients can be attributed to the RV144 vaccine as this was a randomized and double-blinded trial. CD8 and CD4 T cell epitope repertoires were predicted in HIV-1 proteomes from 110 RV144 participants. Predicted Gag epitope repertoires were smaller in vaccine than in placebo recipients (p = 0.019). After comparing participant-derived epitopes to corresponding epitopes in the RV144 vaccine, the proportion of epitopes that could be matched differed depending on the protein conservation (only 36% of epitopes in Env vs 84-91% in Gag/Pol/Nef for CD8 predicted epitopes) or on vaccine insert subtype (55% against CRF01_AE vs 7% against subtype B). To compare predicted epitopes to the vaccine, we analyzed predicted binding affinity and evolutionary distance measurements. Comparisons between the vaccine and placebo arm did not reveal robust evidence for a T cell driven sieve effect, although some differences were noted in Env-V2 (0.022≤p-value≤0.231). The paucity of CD8 T cell responses identified following RV144 vaccination, with no evidence for V2 specificity, considered together both with the association of decreased infection risk in RV 144 participants with V-specific antibody responses and a V2 sieve effect, lead us to hypothesize that this sieve effect was not T cell specific. Overall, our results did not reveal a strong differential impact of vaccine-induced T cell responses among breakthrough infections in RV144 participants.

Trial registration: ClinicalTrials.gov NCT00223080.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist. KD, GK, ST, ESB, SRK, MLR, NLM, JHK, and MR are employees of the US Military HIV Research Program (MHRP). The opinions expressed herein are those of the authors and should not be construed as official or representing the views of the US Department of Defense or the Department of the Army. JMC is an employee of Microsoft Research. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Figures

Figure 1. Flowchart diagram of HIV-1 breakthrough infections in RV144.

Figure 2. Schematic representation of epitope predictions in RV144 HIV-1 breakthrough sequences, and their comparison to RV144 vaccine inserts.

A. Each line represents the Env-gp120 sequence from a subject and each circle a CD8 epitope prediction (different colors for different HLA alleles). The figure represents epitopes predicted based on each subject’s HLA class I genotype for two subjects who were infected with a nearly identical virus (AA100: HLA-A*02∶03, HLA-A*24∶10, HLA-B*18∶01, HLA-B*18∶02, HLA-C*07∶04; AA118: HLA-A*11∶01, HLA-A*24∶07, HLA-B*44∶03, HLA-C*01∶02, HLA-C*07∶01). B. Epitope repertoires from a given subject are compared to the epitope predictions for the vaccine insert sequences (CM244 and MN) based on that subject’s HLA class I genotype. Empty circles represent epitopes predicted in the sequence from a subject that could not be matched to a corresponding epitope prediction based on the vaccine insert sequence and the subject’s HLA class I genotype. More subject-derived epitopes were matched against the vaccine insert CM244 than against MN; both subjects were infected by a CRF01-AE virus like CM244, while MN is a subtype B virus.

Figure 3. Overlap between predicted CD8 and CD4 epitopes in Env-V2 and -V3 in sequences from HIV-1-infected RV144 participants.

The x-axis corresponds to the V2 and V3 sequence, and the y-axis corresponds to the number of predicted epitopes starting at each position. The epitope predictions correspond to all unique HLA/peptide combinations, hence the number of epitope predictions starting at a specific location can surpass the number of subjects in the cohort because a given peptide can be predicted as an epitope for multiple HLA alleles. The amino acids in red correspond to sites that were identified as genetic signatures that distinguished breakthrough sequences from vaccine and placebo recipients.