Cellular immune correlates analysis of an HIV-1 preexposure prophylaxis trial

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Kuebler, Peter J. ; Mehrotra, Megha L. ; McConnell, J. Jeff ; Holditch, Sara J. ; Shaw, Brian I. ; Tarosso, Leandro F. ; Leadabrand, Kaitlyn S. ; Milush, Jeffrey M. ; York, Vanessa A. ; Raposo, Rui Andre Saraiva ; Cheng, Rex G. ; Eriksson, Emily M. ; McMahan, Vanessa ; Glidden, David V. ; Shiboski, Stephen ; Grant, Robert M. ; Nixon, Douglas F. ; Kallas, Esper G.

• Document type: Journal article
• Source: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA; v. 112, n. 27, p. 6-pg., 2015-07-07.

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-gamma enzyme-linked immunospot (ELISpot) assay. IFN-gamma 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-gamma 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. (AU)

• FAPESP's process: 10/05845-0 - Cellular immune responses in infectious diseases and primary immunodeficiencies
• Grantee: Esper Georges Kallás
• Support Opportunities: Research Grants - Visiting Researcher Grant - International
• FAPESP's process: 04/15856-9 - Prospective analysis of the virological and immunological characteristics in individuals with recent HIV-1 infection in the cities of São Paulo and Santos
• Grantee: Ricardo Sobhie Diaz
• Support Opportunities: Research Projects - Thematic Grants