In early simian immunodeficiency virus (SIV) and human immunodeficiency virus-1 (HIV-1) infections, gut-associated lymphatic tissue (GALT), the largest component of the lymphoid organ system, is a principal site of both virus production and depletion of primarily lamina propria memory CD4+ T cells; that is, CD4-expressing T cells that previously encountered antigens and microbes and homed to the lamina propria of GALT. Here, we show that peak virus production in gut tissues of SIV-infected rhesus macaques coincides with peak numbers of infected memory CD4+ T cells. Surprisingly, most of the initially infected memory cells were not, as expected, activated but were instead immunophenotypically 'resting' cells that, unlike truly resting cells, but like the first cells mainly infected at other mucosal sites and peripheral lymph nodes, are capable of supporting virus production. In addition to inducing immune activation and thereby providing activated CD4+ T-cell targets to sustain infection, virus production also triggered an immunopathologically limiting Fas-Fas-ligand-mediated apoptotic pathway in lamina propria CD4+ T cells, resulting in their preferential ablation. Thus, SIV exploits a large, resident population of resting memory CD4+ T cells in GALT to produce peak levels of virus that directly (through lytic infection) and indirectly (through apoptosis of infected and uninfected cells) deplete CD4+ T cells in the effector arm of GALT. The scale of this CD4+ T-cell depletion has adverse effects on the immune system of the host, underscoring the importance of developing counter-measures to SFV that are effective before infection of GALT.
Bibliographical noteFunding Information:
Acknowledgements The authors are grateful to M.-H. Courtier, E. Leclerc and A. Tonon for technical assistance, P. Marynen and J. Cools for providing the human JAK2 cDNA, and J. Feunteun, F. Wendling and O. Bernard for scientific discussions. We thank I. Teyssandier and C. Marzac for their help in collecting polycythaemia vera samples, and J.-C. Brouet, S. Cheze, J.-J. Kiladjian, F. Lellouche, M. Leporrier, M. Macro, P. Morel, O. Reman, L. Roy, A.-L. Taksin, B. Varet and J.-P. Vilque for their help in collecting samples and clinical data. We are also grateful to the patients for their agreement in participating in this study. This work was supported by grants from La Ligue Nationale contre le Cancer (équipe labellisée 2003), la Fédération belge contre le cancer and the FNRS, Belgium. C.J. was supported by a fellowship from the Fondation pour la Recherche Médicale. J.S. was a recipient of a Marie Curie fellowship and of a Daimler-Benz PhD fellowship. S.N.C. is a Research Associate of the FNRS. W.V. is supported by an interface contract between INSERM and IGR.
Acknowledgements We thank R. Veazey, L. Picker, J. Lifson, D. Douek and M. Roederer for discussions; L. Compton, D. Lu, B. Vang, K. Bost and R. Dizon of the Immunology Core Laboratory and Primate Services Unit at the CNPRC for technical assistance; and T. Leonard and C. O’Neill for help in preparing the figures and manuscript. This work was supported by grants from the National Institute of Allergy and Infectious Diseases and from the National Center for Research Resources.