Letters to Nature

Nature 434, 1148-1152 (28 April 2005) | doi:10.1038/nature03513; Received 6 December 2004; Accepted 7 March 2005; Published online 27 March 2005

Peak SIV replication in resting memory CD4+ T cells depletes gut lamina propria CD4+ T cells

Qingsheng Li1, Lijie Duan1, Jacob D. Estes1, Zhong-Min Ma4, Tracy Rourke4, Yichuan Wang4, Cavan Reilly2, John Carlis3, Christopher J. Miller4,5 & Ashley T. Haase1

  1. Department of Microbiology, Medical School, University of Minnesota, MMC 196, 420 Delaware Street S.E.,
  2. Division of Biostatistics, School of Public Health, University of Minnesota, MMC 303, 420 Delaware Street S.E., and
  3. Department of Computer Science and Engineering, Institute of Technology, University of Minnesota, 200 Union Street S.E., Minneapolis, Minnesota 55455, USA
  4. California National Primate Research Center and Center for Comparative Medicine, and
  5. Department of Pathology, Microbiology and Immunology, School of Veterinary Medicine, and Division of Infectious Diseases, School of Medicine, University of California, Davis, California 95616, USA

Correspondence to: Ashley T. Haase1 Correspondence and requests for materials should be addressed to A.T.H. (Email: haase001@umn.edu).

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 system1, 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 GALT2, 3, 4, 5, 6, 7, 8, 9. 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 expected10, 11, 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 nodes12, 13, 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 triggered14 an immunopathologically limiting Fas–Fas-ligand-mediated apoptotic pathway15, 16 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 countermeasures to SIV that are effective before infection of GALT.


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