title: MRKAd5 HIV-1 Gag/Pol/Nef vaccine-induced T-cell responses inadequately predict distance of breakthrough HIV-1 sequences to the vaccine or viral load.
abstract: BACKGROUND
  The sieve analysis for the Step trial found evidence that breakthrough HIV-1 sequences for MRKAd5/HIV-1 Gag/Pol/Nef vaccine recipients were more divergent from the vaccine insert than placebo sequences in regions with predicted epitopes. We linked the viral sequence data with immune response and acute viral load data to explore mechanisms for and consequences of the observed sieve effect.
  
  
  METHODS
  Ninety-one male participants (37 placebo and 54 vaccine recipients) were included; viral sequences were obtained at the time of HIV-1 diagnosis. T-cell responses were measured 4 weeks post-second vaccination and at the first or second week post-diagnosis. Acute viral load was obtained at RNA-positive and antibody-negative visits.
  
  
  RESULTS
  Vaccine recipients had a greater magnitude of post-infection CD8+ T cell response than placebo recipients (median 1.68% vs 1.18%; p = 0·04) and greater breadth of post-infection response (median 4.5 vs 2; p = 0·06). Viral sequences for vaccine recipients were marginally more divergent from the insert than placebo sequences in regions of Nef targeted by pre-infection immune responses (p = 0·04; Pol p = 0·13; Gag p = 0·89). Magnitude and breadth of pre-infection responses did not correlate with distance of the viral sequence to the insert (p>0·50). Acute log viral load trended lower in vaccine versus placebo recipients (estimated mean 4·7 vs 5·1) but the difference was not significant (p = 0·27). Neither was acute viral load associated with distance of the viral sequence to the insert (p>0·30).
  
  
  CONCLUSIONS
  Despite evidence of anamnestic responses, the sieve effect was not well explained by available measures of T-cell immunogenicity. Sequence divergence from the vaccine was not significantly associated with acute viral load. While point estimates suggested weak vaccine suppression of viral load, the result was not significant and more viral load data would be needed to detect suppression.
authors.affiliation: Division of Vaccines and Infectious Diseases, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Holly
authors.initials: H
authors.lastname: Janes
authors.forename: Nicole
authors.initials: N
authors.lastname: Frahm
authors.forename: Allan
authors.initials: A
authors.lastname: DeCamp
authors.forename: Morgane
authors.initials: M
authors.lastname: Rolland
authors.forename: Erin
authors.initials: E
authors.lastname: Gabriel
authors.forename: Julian
authors.initials: J
authors.lastname: Wolfson
authors.forename: Tomer
authors.initials: T
authors.lastname: Hertz
authors.forename: Esper
authors.initials: E
authors.lastname: Kallas
authors.forename: Paul
authors.initials: P
authors.lastname: Goepfert
authors.forename: David P
authors.initials: DP
authors.lastname: Friedrich
authors.forename: Lawrence
authors.initials: L
authors.lastname: Corey
authors.forename: James I
authors.initials: JI
authors.lastname: Mullins
authors.forename: M Juliana
authors.initials: MJ
authors.lastname: McElrath
authors.forename: Peter
authors.initials: P
authors.lastname: Gilbert
mesh_terms: D016915:AIDS Vaccines / Q000627:therapeutic use*; D000328:Adult; D000483:Alleles; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D004279:DNA, Viral / Q000378:metabolism; D000939:Epitopes / Q000737:chemistry; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D007107:Immune System; D008297:Male; D008875:Middle Aged; D013601:T-Lymphocytes / Q000166:cytology*; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*; D054302:pol Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: D016915:AIDS Vaccines; D004279:DNA, Viral; D000939:Epitopes; D054301:gag Gene Products, Human Immunodeficiency Virus; D054311:nef Gene Products, Human Immunodeficiency Virus; D054302:pol Gene Products, Human Immunodeficiency Virus