In Vitro Priming Recapitulates In Vivo HIV-1 Specific T Cell Responses, Revealing Rapid Loss of Virus Reactive + CD4 T Cells in Acute HIV-1 Infection Rachel Lubong Sabado 1 , Daniel G. Kavanagh 2 , Daniel E. Kaufmann2, Karlhans Fru4, Ethan Babcock1, Eric Rosenberg2, Bruce Walker2, Jeffrey Lifson 3 , Nina Bhardwaj1, Marie Larsson 4 * 1 New York University School of Medicine, New York, New York, United States of America, 2 Partners AIDS Research Center (PARC), Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, United States of America, 3 SAIC Fredrick, Inc., National Cancer Institute, Fredrick, Frederick, Maryland, United States of America, 4 Molecular Virology, Department of Clinical and Experimental Medicine, Linko¨ ping University, Linko¨ ping, Sweden Abstract Background: The requirements for priming of HIV-specific T cell responses initially seen in infected individuals remain to be defined. Activation of T cell responses in lymph nodes requires cell-cell contact between T cells and DCs, which can give concurrent activation of T cells and HIV transmission. Methodology: The study aim was to establish whether DCs pulsed with HIV-1 could prime HIV-specific T cell responses and to characterize these responses. Both infectious and aldrithiol-2 inactivated noninfectious HIV-1 were compared to establish efficiencies in priming and the type of responses elicited. Findings: Our findings show that both infectious and inactivated HIV-1 pulsed DCs can prime HIV-specific responses from na¨ıve T cells. Responses included several CD4+ and CD8+ T cell epitopes shown to be recognized in vivo by acutely and chronically infected individuals and some CD4+ T cell epitopes not identified previously. Follow up studies of acute and recent HIV infected samples revealed that these latter epitopes are among the earliest recognized in vivo, but the responses are lost rapidly, presumably through activation-induced general CD4+ T cell depletion which renders the newly activated HIV-specific CD4+ T cells prime targets for elimination. Conclusion: Our studies highlight the ability of DCs to efficiently prime na¨ıve T cells and induce a broad repertoire of HIV- specific responses and also provide valuable insights to the pathogenesis of HIV-1 infection in vivo. Citation: Lubong Sabado R, Kavanagh DG, Kaufmann DE, Fru K, Babcock E, et al. (2009) In Vitro Priming Recapitulates In Vivo HIV-1 Specific T Cell Responses, Revealing Rapid Loss of Virus Reactive CD4+ T Cells in Acute HIV-1 Infection. PLoS ONE 4(1): e4256. doi:10.1371/journal.pone.0004256 Editor: Derya Unutmaz, New York University School of Medicine, United States of America Received October 23, 2008; Accepted December 13, 2008; Published January 23, 2009 Copyright: 2009 Lubong Sabado et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: All below funders have provided funding for performing this study. This work has been supported by grants through: ML: AI52731, The Swedish Research Council, The Swedish, Physicians against AIDS research Foundation, The Swedish International Development Cooperation Agency; SIDA SARC, VINNMER for Vinnova, Linko¨ ping University hospital research Fund, C ALF, and The Swedish Society of Medicine. NB: Emerald Foundation, Burroughs Wellcome, Elizabeth Glaser Pediatric AIDS Foundation, Bill and Melinda Gates Foundation and the Center for HIV/AIDS Vaccine Initiative (CHAVI) and NIH grants AI52731, AI55274, AI61684, AI57127, and AI44628. JL: with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400. The content of this publication does not necessarily reflect the views of policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. Competing Interests: The authors have declared that no competing interests exist. * E-mail: marla@imk.liu.se Introduction HIV-specific cellular immune responses play a central role in controlling HIV-1 replication and in delaying disease progression in infected individuals. The importance of CD4+ and CD8+ T cell responses is highlighted in longterm nonprogressors (LTNPs), whose ability to control infection is correlated with the presence of strong and broadly directed HIV-specific T cell responses [1,2,3]. The presence of activated and proliferating CD4+ CCR5+ gag specific T cells, expressing perforin and granzyme B, in early primary infection supports a potential role for them in helping to control viral replication [4]. However, these T cells disappear as the infection progresses. Similar virus-specific perforin expressing CD4+ T cells exist in rhesus macaques infected with attenuated strains of SIV which protected them from virulent wild type virus challenge [5]. These studies highlight the important role T cells, more specifically CD4+ T cells, can play in determining the course of infection. Dendritic cells (DCs) are the only APC capable of priming na¨ıve T cells in vivo and turning them into long-lasting functional memory T cells. The magnitude and strength of a generated T cell response is based on the quality of the initial priming event, which in turn depends on several factors including trafficking of DCs to lymph node[6] and the quality of the initial DC-T cell interaction[7]. Vaccine studies have demonstrated that it is possible to activate already existing memory cells and prime new T cell responses in vivo [8,9,10]. A recent study used an autologous vaccine consisting of DC pulsed ex vivo with AT-2 inactivated HIV-1 (AT-2 HIV-1) provided promising data with induction of increased levels of HIV-specific T cells and decreased viral load in chronically infected subjects[10]. PLoS ONE | www.plosone.org 1 January 2009 | Volume 4 | Issue 1 | e4256