Peak SIV replication in resting memory CD4+ T cells depletes gut lamina propria CD4+ T cells (original) (raw)

Nature volume 434, pages 1148–1152 (2005)Cite this article

Abstract

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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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.

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Authors and Affiliations

  1. Department of Microbiology, Medical School, University of Minnesota, MMC 196, 420 Delaware Street S.E., Minneapolis, Minnesota, 55455, USA
    Qingsheng Li, Lijie Duan, Jacob D. Estes & Ashley T. Haase
  2. Division of Biostatistics, School of Public Health, University of Minnesota, MMC 303, 420 Delaware Street S.E., Minneapolis, Minnesota, 55455, USA
    Cavan Reilly
  3. Department of Computer Science and Engineering, Institute of Technology, University of Minnesota, 200 Union Street S.E., Minneapolis, Minnesota, 55455, USA
    John Carlis
  4. California National Primate Research Center and Center for Comparative Medicine, University of California, Davis, California, 95616, USA
    Zhong-Min Ma, Tracy Rourke, Yichuan Wang & Christopher J. Miller
  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
    Christopher J. Miller

Authors

  1. Qingsheng Li
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  2. Lijie Duan
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  3. Jacob D. Estes
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  4. Zhong-Min Ma
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  5. Tracy Rourke
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  6. Yichuan Wang
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  7. Cavan Reilly
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  8. John Carlis
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  9. Christopher J. Miller
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  10. Ashley T. Haase
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Correspondence toAshley T. Haase.

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Li, Q., Duan, L., Estes, J. et al. Peak SIV replication in resting memory CD4+ T cells depletes gut lamina propria CD4+ T cells.Nature 434, 1148–1152 (2005). https://doi.org/10.1038/nature03513

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Editorial Summary

HIV: stop it in its tracks

Two papers in this issue shed light on the early stages of HIV infection. HIV gradually infects and destroys disease-fighting CD4+ T cells in the blood, but also causes loss of CD4+ T cells from mucosal surfaces such as the gut in the initial infection phase. Studies in monkeys infected with simian immunodeficiency virus (SIV) now show that the virus infects and kills memory CD4+ T cells, a T-cell subset responsible for remembering previous infections. Mattapallil et al. found that SIV infects about 50% of memory CD4+ T cells within days of infection. Li et al. show that as well as killing by direct infection, the virus triggers uninfected cells to self-destruct via apoptosis. These findings have clinical implications, stressing the need to reduce viral load at the early stage of infection.

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