Peak SIV replication in resting memory CD4+ T cells depletes gut lamina propria CD4+ T cells (original) (raw)
- Letter
- Published: 27 March 2005
- Lijie Duan1,
- Jacob D. Estes1,
- Zhong-Min Ma4,
- Tracy Rourke4,
- Yichuan Wang4,
- Cavan Reilly2,
- John Carlis3,
- Christopher J. Miller4,5 &
- …
- Ashley T. Haase1
Nature volume 434, pages 1148–1152 (2005)Cite this article
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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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References
- Mowat, A. M. & Viney, J. L. The anatomical basis of intestinal immunity. Immunol. Rev. 156, 145–166 (1997)
Article CAS Google Scholar - Veazey, R. S. et al. Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection. Science 280, 427–431 (1998)
Article ADS CAS Google Scholar - Kewenig, S. et al. Rapid CD4+ T cell depletion and enteropathy in simian immunodeficiency virus infected rhesus macaques. Gastroenterology 116, 1115–1123 (1999)
Article CAS Google Scholar - Schneider, T. et al. Loss of CD4 T lymphocytes in patients infected with human immunodeficiency virus type 1 is more pronounced in the duodenal mucosa than in the peripheral blood. Gut 37, 524–529 (1995)
Article CAS Google Scholar - Mehandru, S. et al. Primary HIV-1 infection is associated with preferential depletion of CD4+ T lymphocytes from effector sites in the gastrointestinal tract. J. Exp. Med. 200, 761–770 (2004)
Article CAS Google Scholar - Brenchley, J. M. et al. CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract. J. Exp. Med. 200, 749–759 (2004)
Article CAS Google Scholar - Guadalupe, M. et al. Severe CD4+ T-cell depletion in gut lymphoid tissue during primary human immunodeficiency virus type 1 infection and substantial delay in restoration following highly active antiretroviral therapy. J. Virol. 77, 11708–11717 (2003)
Article CAS Google Scholar - Clayton, F., Snow, G., Reka, S. & Kotler, D. P. Selective depletion of rectal lamina propria rather than lymphoid aggregate CD4 lymphocytes in HIV infection. Clin. Exp. Immunol. 107, 288–292 (1997)
Article CAS Google Scholar - Lim, S. G. et al. Loss of mucosal CD4 lymphocytes is an early feature of HIV infection. Clin. Exp. Immunol. 92, 448–454 (1993)
Article CAS Google Scholar - Veazey, R. & Lackner, A. The mucosal immune system and HIV-1 infection. AIDS Rev. 5, 245–252 (2003)
Google Scholar - Veazey, R. et al. Identifying the target cell in primary simian immunodeficiency virus infection: Highly activated memory CD4+ T cells are rapidly eliminated in early SIV infection in vivo . J. Virol. 74, 57–64 (2000)
Article CAS Google Scholar - Zhang, Z.-Q. et al. Sexual transmission and propagation of simian and human immunodeficiency viruses in two distinguishable populations of CD4+ T cells. Science 286, 1353–1357 (1999)
Article CAS Google Scholar - Zhang, Z.-Q. et al. Roles of substrate availability and infection of resting and activated CD4+ T cells in transmission and acute simian immunodeficiency virus infection. Proc. Natl Acad. Sci. USA 101, 5640–5645 (2004)
Article ADS CAS Google Scholar - Boirivant, M. et al. HIV-1 gp120 accelerates Fas-mediated activation-induced human lamina propria T cell apoptosis. J. Clin. Immunol. 18, 39–47 (1998)
Article CAS Google Scholar - Boirivant, M. et al. Stimulated human lamina propria T cells manifest enhanced Fas-mediated apoptosis. J. Clin. Invest. 98, 2616–2622 (1996)
Article CAS Google Scholar - De Maria, R. et al. Functional expression of Fas and Fas ligand on human gut lamina propria T lymphocytes. A potential role for the acidic sphingomyelinase pathway in normal immunoregulation. J. Clin. Invest. 97, 316–322 (1996)
Article CAS Google Scholar - Testi, R., Phillips, J. H. & Lanier, L. L. Constitutive expression of a phosphorylated activation antigen (Leu 23) by CD3 bright human thymocytes. J. Immunol. 141, 2557–2563 (1988)
CAS PubMed Google Scholar - Testi, R., Phillips, J. H. & Lanier, L. L. Leu 23 induction as an early marker of functional CD3/T cell antigen receptor triggering. Requirement for receptor cross-linking, prolonged elevation of intracellular [Ca + + ] and stimulation of protein kinase C. J. Immunol. 142, 1854–1860 (1989)
CAS PubMed Google Scholar - Phillips, A. N. Reduction of HIV concentration during acute infection: independence from a specific immune response. Science 271, 497–499 (1996)
Article ADS CAS Google Scholar - Reilly, C. S. et al. The clustering of SIV infected cells in lymphatic tissue. J. Am. Stat. Assoc. 97, 943–954 (2002)
Article Google Scholar - Mothe, B. R. et al. Dominance of CD8 responses specific for epitopes bound by a single major histocompatibility complex class I molecule during the acute phase of viral infection. J. Virol. 76, 875–884 (2002)
Article CAS Google Scholar - Reynolds, M. R. et al. The CD8+ lymphocyte response to major immunodominant epitopes after vaginal exposure to SIV: too late and too little. J. Virol (in the press)
- Pope, M. & Haase, A. T. Transmission, acute HIV-1 infection and the quest for effective vaccines, microbicides and other strategies to prevent infection. Nature Med. 9, 847–852 (2003)
Article CAS Google Scholar - Miller, C. J. et al. Intravaginal inoculation of rhesus macaques with cell-free simian immunodeficiency virus results in persistent or transient viremia. J. Virol. 68, 6391–6400 (1994)
CAS PubMed PubMed Central Google Scholar - Poppema, S., Lai, R. & Visser, L. Monoclonal antibody OPD4 is reactive with CD45RO, but differs from UCHL1 by the absence of monocyte reactivity. Am. J. Pathol. 139, 725–729 (1991)
CAS PubMed PubMed Central Google Scholar - Miller, C. J. et al. Propagation and dissemination of infection after vaginal transmission of SIV. J. Virol (submitted)
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
- 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 - Division of Biostatistics, School of Public Health, University of Minnesota, MMC 303, 420 Delaware Street S.E., Minneapolis, Minnesota, 55455, USA
Cavan Reilly - Department of Computer Science and Engineering, Institute of Technology, University of Minnesota, 200 Union Street S.E., Minneapolis, Minnesota, 55455, USA
John Carlis - 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 - 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
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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
- Received: 06 December 2004
- Accepted: 07 March 2005
- Published: 27 March 2005
- Issue Date: 28 April 2005
- DOI: 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.