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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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.
The authors declare that they have no competing financial interests.
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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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