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Blood, 29 October 2009, Vol. 114, No. 18, pp. 3723-3724. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Cerutti, A. PubMed PubMed Citation Articles by Cerutti, A. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Comment on Stary et al, page 3854 HIV infection: TRAILing the killers Andrea Cerutti CORNELL UNIVERSITY Progressive loss of CD4+ T cells is a hallmark of HIV infection, but its mechanism remains poorly understood. In this issue of Blood, Stary and colleagues show that CD4+ T cells from viremic patients undergo apoptosis in response to death-inducing signals generated by TRAIL expressed on the surface of plasmacytoid dendritic cells. HIV infection is characterized by progressive depletion of both infected and uninfected CD4+ T cells, which leads to the development of AIDS. Increased apoptosis is regarded as the primary cause of HIV-induced CD4+ T-cell loss, and multiple mechanisms have been brought forward to explain the immunopathogenesis of this apoptotic process.1 Whereas direct cytopathic effects affect the survival of infected CD4+ T cells, indirect mechanisms, such as activation-induced cell death, are likely to play a major role in the elimination of uninfected CD4+ T cells.2,3 Activation-induced cell death may involve an augmented responsiveness of CD4+ T cells to various inhibitory and death-inducing ligands such as PD-1L, CTLA-4, and FasL.4,5 Recent evidence points to an additional contribution of TNF-related apoptosis-inducing ligand (TRAIL).6 Soluble TRAIL is elevated in the plasma of HIV-infected patients and CD4+ T cells from these patients are more sensitive to TRAIL-induced death signals. A possible source of TRAIL is plasmacytoid dendritic cells (pDCs), a professional interferon (IFN)–producing dendritic cell subset that usually plays a key role in antiviral immunity.6 In infected patients, pDCs release massive amounts of IFN- in response to HIV, but cannot achieve the control of the infection. Rather, in vitro studies indicate that pDCs up-regulate TRAIL expression in response to HIV-induced IFN- and thereafter acquire cytotoxic activity on bystander CD4+ T cells.6 Of note, the up-regulation of TRAIL expression by HIV-exposed pDCs is highly dependent on sensing viral single-stranded RNA through the intracellular sensor Toll-like receptor 7 (TLR7).6 In this issue, Stary and colleagues sought to extend these in vitro findings to an in vivo setting and explored the presence of TRAIL-expressing killer pDCs in HIV-infected persons.7 They found that pDCs and CD4+ T cells from infected patients expressed TRAIL and its cognate receptor TRAIL-R1, respectively. TRAIL expression directly correlated with viremia, whereas there was an inverse correlation between TRAIL-expressing pDCs and CD4+ T cells. Remarkably, TRAIL-expressing pDCs were proximal to apoptotic CD4+ T cells in tissue sections from systemic lymph nodes. In vitro, pDCs from viremic patients, but not pDCs from aviremic or noninfected persons, triggered death of activated CD4+ T cells through a mechanism that required TRAIL and to a lesser extent IFN-. This study clearly shows that TRAIL-expressing killer pDCs are present in vivo and likely play an important role in the loss of CD4+ T cells. Stary and colleagues' findings also raise intriguing questions. For instance, it is remarkable that, although expressing comparable or higher surface levels of TRAIL, monocytes and myeloid dendritic cells (mDCs) from viremic patients do not have cytotoxic activity on activated CD4+ T cells. One possible interpretation is that monocytes and mDCs lack surface molecules with immunoregulatory activity required for TRAIL to deliver optimal cytotoxic signals to targeted CD4+ T cells. Another interesting aspect is the up-regulation of surface TRAIL-R1 but not TRAIL-R2, TRAIL-R3, and TRAIL-R4 by CD4+ T cells from viremic patients.7 What is the mechanism by which HIV selectively augments TRAIL-R1 expression? And why does TRAIL-R1 up-regulation occur on CD4+ T cells but not on other cell types such as monocytes? One possibility is that monocytes express constitutively high levels of TRAIL and are not susceptible to further up-regulation. At any rate, the present work clearly suggests that HIV alters the responsiveness of CD4+ T cells to TRAIL-induced signals by perturbing the normal balance between death-inducing (R1 and R2) and regulatory (R3 and R4) TRAIL receptors on the surface of CD4+ T cells.7 Yet, the mechanism behind the establishment of this receptor imbalance remains puzzling. Furthermore, the expression of TRAIL and TRAIL-R1 by intestinal pDCs and CD4+ T cells, respectively, remains unknown. In both HIV-infected humans and SIV-infected macaques, CD4+ T cells undergo early and massive death in the intestinal mucosa.1,8,9 This mucosal catastrophe causes systemic leakage of intestinal antigens, which in turn promotes dysregulated systemic immune activation.1,2 Thus, a top future priority will be to address the presence, phenotype, and function of TRAIL-expressing killer pDCs and TRAIL-R1 CD4+ T cells in the intestinal mucosa of acutely and chronically infected HIV patients. Footnotes Conflict-of-interest disclosure: The author declares no competing financial interests. REFERENCES Douek DC, Roederer M, Koup RA. Emerging concepts in the immunopathogenesis of AIDS. Annu Rev Med. 2009;60:471–484.[CrossRef][Medline] [Order article via Infotrieve] Brenchley JM, Price DA, Schacker TW, et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med. 2006;12(12):1365–1371.[Medline] [Order article via Infotrieve] Sodora DL, Allan JS, Apetrei C, et al. Toward an AIDS vaccine: lessons from natural simian immunodeficiency virus infections of African nonhuman primate hosts. Nat Med. 2009;15(8):861–865.[CrossRef][Medline] [Order article via Infotrieve] Fluur C, De Milito A, Fry TJ, et al. Potential role for IL-7 in Fas-mediated T cell apoptosis during HIV infection. J Immunol. 2007;178(8):5340–5350.[Abstract/Free Full Text] Kaufmann DE, Walker BD. PD-1 and CTLA-4 inhibitory cosignaling pathways in HIV infection and the potential for therapeutic intervention. J Immunol. 2009;182(10):5891–5897.[Abstract/Free Full Text] Hardy AW, Graham DR, Shearer GM, Herbeuval JP. HIV turns plasmacytoid dendritic cells (pDC) into TRAIL-expressing killer pDC and down-regulates HIV coreceptors by Toll-like receptor 7-induced IFN-alpha. Proc Natl Acad Sci U S A. 2007;104(44):17453–17458.[Abstract/Free Full Text] Stary G, Klein I, Kohlhofer S, et al. Plasmacytoid dendritic cells express TRAIL and induce CD4+ T-cell apoptosis in HIV-1 viremic patients. Blood. 2009;114(18):3854–3863.[Abstract/Free Full Text] Veazey RS, DeMaria M, Chalifoux LV, et al. Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection. Science. 1998;280(5362):427–431.[Abstract/Free Full Text] Brenchley JM, Schacker TW, Ruff LE, et al. CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract. J Exp Med. 2004;200(6):749–759.[Abstract/Free Full Text] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Plasmacytoid dendritic cells express TRAIL and induce CD4+ T-cell apoptosis in HIV-1 viremic patients Georg Stary, Irene Klein, Sabine Kohlhofer, Frieder Koszik, Thomas Scherzer, Leonhard Müllauer, Heribert Quendler, Norbert Kohrgruber, and Georg Stingl Blood 2009 114: 3854-3863. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Cerutti, A. 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