title: Immune-correlates analysis of an HIV-1 vaccine efficacy trial reveals an association of nonspecific interferon-γ secretion with increased HIV-1 infection risk: a cohort-based modeling study.
abstract: BACKGROUND
  Elevated risk of HIV-1 infection among recipients of an adenovirus serotype 5 (Ad5)-vectored HIV-1 vaccine was previously reported in the Step HIV-1 vaccine efficacy trial. We assessed pre-infection cellular immune responses measured at 4 weeks after the second vaccination to determine their roles in HIV-1 infection susceptibility among Step study male participants.
  
  
  METHODS
  We examined ex vivo interferon-γ (IFN-γ) secretion from peripheral blood mononuclear cells (PBMC) using an ELISpot assay in 112 HIV-infected and 962 uninfected participants. In addition, we performed flow cytometric assays to examine T-cell activation, and ex vivo IFN-γ and interleukin-2 secretion from CD4(+) and CD8(+) T cells. We accounted for the sub-sampling design in Cox proportional hazards models to estimate hazard ratios (HRs) of HIV-1 infection per 1-log(e) increase of the immune responses.
  
  
  RESULTS
  We found that HIV-specific immune responses were not associated with risk of HIV-1 infection. However, each 1-log(e) increase of mock responses measured by the ELISpot assay (i.e., IFN-γ secretion in the absence of antigen-specific stimulation) was associated with a 62% increase of HIV-1 infection risk among vaccine recipients (HR = 1.62, 95% CI: (1.28, 2.04), p<0.001). This association remains after accounting for CD4(+) or CD8(+) T-cell activation. We observed a moderate correlation between ELISpot mock responses and CD4(+) T-cells secreting IFN-γ (ρ = 0.33, p = 0.007). In addition, the effect of the Step vaccine on infection risk appeared to vary with ELISpot mock response levels, especially among participants who had pre-existing anti-Ad5 antibodies (interaction p = 0.04).
  
  
  CONCLUSIONS
  The proportion of cells, likely CD4(+) T-cells, producing IFN-γ without stimulation by exogenous antigen appears to carry information beyond T-cell activation and baseline characteristics that predict risk of HIV-1 infection. These results motivate additional investigation to understand the potential link between IFN-γ secretion and underlying causes of elevated HIV-1 infection risk among vaccine recipients in the Step study.
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America; Public Health Science Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Yunda
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America; Public Health Science Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America; Department of Global Health, University of Washington, Seattle, Washington, United States of America; Department of Epidemiology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Ann
authors.initials: A
authors.lastname: Duerr
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America; Department of Global Health, University of Washington, Seattle, Washington, United States of America.
authors.forename: Nicole
authors.initials: N
authors.lastname: Frahm
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Lily
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America; Public Health Science Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Zoe
authors.initials: Z
authors.lastname: Moodie
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America; Department of Laboratory Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: Steve
authors.initials: S
authors.lastname: De Rosa
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America; Department of Global Health, University of Washington, Seattle, Washington, United States of America; Department of Laboratory Medicine, University of Washington, Seattle, Washington, United States of America; Department of Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: M Juliana
authors.initials: MJ
authors.lastname: McElrath
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America; Public Health Science Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America; Department of Biostatistics, University of Washington, Seattle, Washington, United States of America.
authors.forename: Peter B
authors.initials: PB
authors.lastname: Gilbert
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D015331:Cohort Studies; D005500:Follow-Up Studies; D015658:HIV Infections / Q000473:pathology / Q000517:prevention & control*; D015497:HIV-1 / Q000378:metabolism; D006801:Humans; D007118:Immunoassay; D007371:Interferon-gamma / Q000378:metabolism*; D007376:Interleukin-2 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation; D008297:Male; D016016:Proportional Hazards Models; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D012306:Risk; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D054302:pol Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D016915:AIDS Vaccines; D007376:Interleukin-2; D011994:Recombinant Proteins; D054301:gag Gene Products, Human Immunodeficiency Virus; D054311:nef Gene Products, Human Immunodeficiency Virus; D054302:pol Gene Products, Human Immunodeficiency Virus; D007371:Interferon-gamma