Journal Article

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

Kaewkungwal, Jaranit, Geraghty, Dan E., Deng, Wenjie, O'Connell, Robert J., Mullins, James I., Sanders-Buell, Eric, Nitayaphan, Sorachai, Pitisuttihum, Punnee, Carlson, Jonathan M., Kim, Jerome H., Michael, Nelson L., Robb, Merlin L., Tovanabutra, Sodsai, Ratto-Kim, Silvia, deSouza, Mark S., Rolland, Morgane, Edlefsen, Paul T., Kijak, Gustavo, Maust, Brandon S., Rerks-Ngarm, Supachai, Dommaraju, Kalpana, Larsen, Brendan B.

2014

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Acquired immune deficiency syndrome / Adolescent / Adult / AIDS / AIDS Vaccines - therapeutic use / Alleles / Armed forces / Biology and life sciences / CD4 antigen / CD4-Positive T-Lymphocytes - cytology / CD8 antigen / CD8-Positive T-Lymphocytes - cytology / Conservation / Distance measurement / Epitopes / Epitopes, T-Lymphocyte - chemistry / Female / gag Gene Products, Human Immunodeficiency Virus - chemistry / Gag protein / Genotype / Health risks / HIV / HIV Envelope Protein gp120 - chemistry / HIV Infections - prevention & control / HIV-1 - genetics / HLA Antigens - chemistry / Human immunodeficiency virus / Humans / Immunoglobulins / Infections / Infectious diseases / Lymphocytes / Lymphocytes T / Male / Medical research / Nef protein / Phylogenetics / Predictions / Proteome - chemistry / Public health / Thioglycolates - chemistry / Thiophenes - chemistry / Vaccination / Vaccines / Viruses / Young Adult