title: 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.
authors.affiliation: US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America; Henry Jackson Foundation, Bethesda, Maryland, United States of America.
authors.forename: Kalpana
authors.initials: K
authors.lastname: Dommaraju
authors.affiliation: US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America; Henry Jackson Foundation, Bethesda, Maryland, United States of America.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Kijak
authors.affiliation: Microsoft Research, Los Angeles, California, United States of America.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Carlson
authors.affiliation: Department of Microbiology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Brendan B
authors.initials: BB
authors.lastname: Larsen
authors.affiliation: US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America; Henry Jackson Foundation, Bethesda, Maryland, United States of America.
authors.forename: Sodsai
authors.initials: S
authors.lastname: Tovanabutra
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Dan E
authors.initials: DE
authors.lastname: Geraghty
authors.affiliation: Department of Microbiology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Deng
authors.affiliation: Department of Microbiology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Brandon S
authors.initials: BS
authors.lastname: Maust
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Edlefsen
authors.affiliation: US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America; Henry Jackson Foundation, Bethesda, Maryland, United States of America.
authors.forename: Eric
authors.initials: E
authors.lastname: Sanders-Buell
authors.affiliation: US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America; Henry Jackson Foundation, Bethesda, Maryland, United States of America.
authors.forename: Silvia
authors.initials: S
authors.lastname: Ratto-Kim
authors.affiliation: Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand.
authors.forename: Mark S
authors.initials: MS
authors.lastname: deSouza
authors.affiliation: Thai Ministry of Public Health, Nonthaburi, Thailand.
authors.forename: Supachai
authors.initials: S
authors.lastname: Rerks-Ngarm
authors.affiliation: Royal Thai Army Component, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand.
authors.forename: Sorachai
authors.initials: S
authors.lastname: Nitayaphan
authors.affiliation: Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: Punnee
authors.initials: P
authors.lastname: Pitisuttihum
authors.affiliation: Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: Jaranit
authors.initials: J
authors.lastname: Kaewkungwal
authors.affiliation: Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: O'Connell
authors.affiliation: US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America; Henry Jackson Foundation, Bethesda, Maryland, United States of America.
authors.forename: Merlin L
authors.initials: ML
authors.lastname: Robb
authors.affiliation: US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.
authors.forename: Nelson L
authors.initials: NL
authors.lastname: Michael
authors.affiliation: Department of Microbiology, University of Washington, Seattle, Washington, United States of America.
authors.forename: James I
authors.initials: JI
authors.lastname: Mullins
authors.affiliation: US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.
authors.forename: Jerome H
authors.initials: JH
authors.lastname: Kim
authors.affiliation: US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America; Henry Jackson Foundation, Bethesda, Maryland, United States of America.
authors.forename: Morgane
authors.initials: M
authors.lastname: Rolland
mesh_terms: D016915:AIDS Vaccines / Q000627:therapeutic use*; D000293:Adolescent; D000328:Adult; D000483:Alleles; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology*; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry; D005260:Female; D005838:Genotype; D015699:HIV Envelope Protein gp120 / Q000737:chemistry; D015658:HIV Infections / Q000517:prevention & control*; D015497:HIV-1 / Q000235:genetics*; D006680:HLA Antigens / Q000737:chemistry; D006801:Humans; D008297:Male; D020543:Proteome / Q000737:chemistry; D013864:Thioglycolates / Q000737:chemistry*; D013876:Thiophenes / Q000737:chemistry*; D055815:Young Adult; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000737:chemistry
chemical_list: D016915:AIDS Vaccines; D018984:Epitopes, T-Lymphocyte; D015699:HIV Envelope Protein gp120; D006680:HLA Antigens; D020543:Proteome; D013864:Thioglycolates; D013876:Thiophenes; D054301:gag Gene Products, Human Immunodeficiency Virus; C048498:erdosteine