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* Research Institute for Development, Laboratory of Retroviral and Molecular Immunology, Montpellier, France;
Institut National de la Santé et de la Recherche Médicale, Unité 454, Montpellier, France;
Department of Immunology, Dipartamento di Scienze Precliniche Labovatorio Interdisciplinare di Technologie Avanzate Vialba, Milano University Medical School, Milan, Italy; and
Infectious Diseases Clinic, Santissima Annunziata Hospital, Antella, Firenze, Italy
Certain individuals are resistant to HIV-1 infection, despite repeated exposure to the virus. Although protection against HIV-1 infection in a small proportion of Caucasian individuals is associated with mutant alleles of the CCR5 HIV-1 coreceptor, the molecular mechanism underlying resistance in repeatedly HIV-1-exposed, uninfected individuals (EU) is unclear. In this study, we performed complementary transcriptome and proteome analyses on peripheral blood T cells, and plasma or serum from EU, their HIV-1-infected sexual partners, and healthy controls, all expressing wild-type CCR5. We report that activated T cells from EU overproduce several proteins involved in the innate immunity response, principally those including high levels of peroxiredoxin II, a NK-enhancing factor possessing strong anti-HIV activity, and IL-22, a cytokine involved in the production of acute-phase proteins such as the acute-phase serum amyloid A (A-SAA). Cell supernatants and serum levels of these proteins were up-regulated in EU. Moreover, a specific biomarker for EU detected in plasma was identified as an 8.6-kDa A-SAA cleavage product. Incubation of in vitro-generated myeloid immature dendritic cells with A-SAA resulted in CCR5 phosphorylation, down-regulation of CCR5 expression, and strongly decreased susceptibility of these cells to in vitro infection with a primary HIV-1 isolate. Taken together, these results suggest new correlates of EU protection and identify a cascade involving IL-22 and the acute phase protein pathway that is associated with innate host resistance to HIV infection.
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1 This work was supported by grants from Sidaction France; the Institut de Recherche pour le Développement, France; the Centre National de la Recherche Scientifique, France; the Agence Nationale de Recherches sur le SIDA, France; the Istituto Superiore di Sanita’ "Programma Nazionale di Ricerca sull’ AIDS," Italy; the Centro di Eccellenza Centro Interdisciplinare Studi Bio-molecolari e Applicazioni Industriali, Italy; the European Microbicides Project and AIDS Vaccine Project of the European Commission WP6 Projects; the Japan Health Science Foundation; Fondo per gli Investimenti della Ricerca di Base; and Tuscany Region, Italy, Directorate General Right to Health and Solidarity Policy, Italy.
2 H.Y. and D.T. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Francisco Veas, Laboratory of Retroviral and Molecular Immunology, Research Institute for Development (UR178); 240, Avenue E Jeanbrau, Etablissement Francais du Sang, 34094 Montpellier, France. E-mail address: veas{at}mpl.ird.fr
4 Abbreviation used in this paper: EU, exposed uninfected; HC, healthy control subject; SAGE, serial analysis of gene expression; iDC, immature dendritic cell; FPR, formyl peptide receptor; RT, reverse transcription; SELDI-TOF-MS, surface-enhanced laser desorption ionization and time-of-flight mass spectrophotometer; A-SAA, acute-phase serum amyloid A; SOCS, suppressor of cytokine signaling; PRDX2, peroxiredoxin II.
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