title: Cellular immune correlates analysis of an HIV-1 preexposure prophylaxis trial.
abstract: HIV-1-specific T-cell responses in exposed seronegative subjects suggest that a viral breach of the exposure site is more common than current transmission rates would suggest and that host immunity can extinguish subsequent infection foci. The Preexposure Prophylaxis Initiative (iPrEx) chemoprophylaxis trial provided an opportunity to rigorously investigate these responses in a case-control immunology study; 84 preinfection peripheral blood mononuclear cell samples from individuals enrolled in the iPrEx trial who later seroconverted were matched with 480 samples from enrolled subjects who remained seronegative from both the placebo and active treatment arms. T-cell responses to HIV-1 Gag, Protease, Integrase, Reverse Transcriptase, Vif, and Nef antigens were quantified for all subjects in an IFN-γ enzyme-linked immunospot (ELISpot) assay. IFN-γ responses varied in magnitude and frequency across subjects. A positive response was more prevalent in those who remained persistently HIV-1-negative for Gag (P = 0.007), Integrase (P < 0.001), Vif (P < 0.001), and Nef (P < 0.001). When correlated with outcomes in the iPrEx trial, Vif- and Integrase-specific T-cell responses were associated with reduced HIV-1 infection risk [hazard ratio (HR) = 0.36, 95% confidence interval (95% CI) = 0.19-0.66 and HR = 0.52, 95% CI = 0.28-0.96, respectively]. Antigen-specific responses were independent of emtricitabine/tenofovir disoproxil fumarate use. IFN-γ secretion in the ELISpot was confirmed using multiparametric flow cytometry and largely attributed to effector memory CD4+ or CD8+ T cells. Our results show that HIV-1-specific T-cell immunity can be detected in exposed but uninfected individuals and that these T-cell responses can differentiate individuals according to infection outcomes.
authors.affiliation: Division of Experimental Medicine, University of California, San Francisco, CA 94110; peter.kuebler@ucsf.edu.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Kuebler
authors.affiliation: Institute of Virology & Immunology, Gladstone Institutes, San Francisco, CA 94158;
authors.forename: Megha L
authors.initials: ML
authors.lastname: Mehrotra
authors.affiliation: Institute of Virology & Immunology, Gladstone Institutes, San Francisco, CA 94158;
authors.forename: J Jeff
authors.initials: JJ
authors.lastname: McConnell
authors.affiliation: Division of Experimental Medicine, University of California, San Francisco, CA 94110;
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Holditch
authors.affiliation: Division of Experimental Medicine, University of California, San Francisco, CA 94110;
authors.forename: Brian I
authors.initials: BI
authors.lastname: Shaw
authors.affiliation: Division of Clinical Immunology and Allergy, University of São Paulo, São Paulo, Brazil 01246;
authors.forename: Leandro F
authors.initials: LF
authors.lastname: Tarosso
authors.affiliation: Division of Experimental Medicine, University of California, San Francisco, CA 94110;
authors.forename: Kaitlyn S
authors.initials: KS
authors.lastname: Leadabrand
authors.affiliation: Division of Experimental Medicine, University of California, San Francisco, CA 94110;
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Milush
authors.affiliation: Division of Experimental Medicine, University of California, San Francisco, CA 94110;
authors.forename: Vanessa A
authors.initials: VA
authors.lastname: York
authors.affiliation: Division of Experimental Medicine, University of California, San Francisco, CA 94110; Department of Microbiology, Immunology and Tropical Medicine, George Washington University, Washington, DC 20037;
authors.forename: Rui André Saraiva
authors.initials: RA
authors.lastname: Raposo
authors.affiliation: Division of Experimental Medicine, University of California, San Francisco, CA 94110;
authors.forename: Rex G
authors.initials: RG
authors.lastname: Cheng
authors.affiliation: Division of Experimental Medicine, University of California, San Francisco, CA 94110;
authors.forename: Emily M
authors.initials: EM
authors.lastname: Eriksson
authors.affiliation: Institute of Virology & Immunology, Gladstone Institutes, San Francisco, CA 94158;
authors.forename: Vanessa
authors.initials: V
authors.lastname: McMahan
authors.affiliation: Department of Epidemiology and Biostatistics, University of California, San Francisco, CA 94158;
authors.forename: David V
authors.initials: DV
authors.lastname: Glidden
authors.affiliation: Department of Epidemiology and Biostatistics, University of California, San Francisco, CA 94158;
authors.forename: Stephen
authors.initials: S
authors.lastname: Shiboski
authors.affiliation: Institute of Virology & Immunology, Gladstone Institutes, San Francisco, CA 94158; Department of Medicine, University of California, San Francisco, CA 94143.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Grant
authors.affiliation: Division of Experimental Medicine, University of California, San Francisco, CA 94110; Department of Microbiology, Immunology and Tropical Medicine, George Washington University, Washington, DC 20037;
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Nixon
authors.affiliation: Division of Clinical Immunology and Allergy, University of São Paulo, São Paulo, Brazil 01246;
authors.forename: Esper G
authors.initials: EG
authors.lastname: Kallás
mesh_terms: D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D016022:Case-Control Studies; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D015658:HIV Infections / Q000097:blood / Q000276:immunology* / Q000821:virology; D006679:HIV Seropositivity / Q000276:immunology; D015497:HIV-1 / Q000276:immunology* / Q000378:metabolism / Q000502:physiology; D054298:Human Immunodeficiency Virus Proteins / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007111:Immunity, Cellular / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology* / Q000378:metabolism; D016015:Logistic Models; D008297:Male; D015999:Multivariate Analysis; D055815:Young Adult
chemical_list: D054298:Human Immunodeficiency Virus Proteins; D007371:Interferon-gamma
keywords: HIV-1; T cell; designated HIV-1–exposed seronegative; preexposure chemoprophylaxis; vaccine