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

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

doi:10.1073/pnas.1501443112

Edited by Robert C. Gallo, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, and approved May 27, 2015 (received for review January 22, 2015)

Significance

The demonstration and clinical relevance of HIV-1–specific immune responses in exposed but uninfected seronegative individuals have been controversial. Studies seeking to detect these responses have generally been small in size and have varied in study population, methods of detection, and control groups. We conducted a large case–control immunology study of participants in the Preexposure Prophylaxis Initiative (iPrEx) chemoprophylaxis trial, selecting preinfection time points for those who became infected compared with persistently HIV-1–negative controls. We confirmed that HIV-1–specific responses are present in exposed uninfected individuals, sometimes at very high magnitude. HIV-1–specific responses also correlated with infection risk.

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.

Footnotes

↵¹To whom correspondence should be addressed. Email: peter.kuebler{at}ucsf.edu.
↵²M.L.M., J.J.M., S.J.H., and B.I.S. contributed equally to this work.
↵³Deceased January 25, 2014.
↵⁴Present address: Department of Medical Biology, Walter and Eliza Hall Institute of Medical Research and University of Melbourne, Parkville, VIC 3052, Australia.
↵⁵R.M.G., D.F.N., and E.G.K. contributed equally to this work as senior authors.

Author contributions: P.J.K., M.L.M., J.J.M., S.J.H., B.I.S., L.F.T., R.G.C., E.M.E., V.M., D.V.G., S.S., R.M.G., D.F.N., and E.G.K. designed research; P.J.K., M.L.M., S.J.H., B.I.S., L.F.T., K.S.L., J.M.M., V.A.Y., R.A.S.R., and D.V.G. performed research; M.L.M., J.M.M., V.A.Y., D.V.G., and S.S. contributed new reagents/analytic tools; P.J.K., M.L.M., J.J.M., S.J.H., B.I.S., L.F.T., K.S.L., V.A.Y., D.V.G., S.S., R.M.G., D.F.N., and E.G.K. analyzed data; and P.J.K., M.L.M., J.J.M., S.J.H., B.I.S., L.F.T., K.S.L., J.M.M., V.A.Y., R.A.S.R., R.G.C., E.M.E., V.M., D.V.G., S.S., R.M.G., D.F.N., and E.G.K. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
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