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

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 GALT^{2,3,4,5,6,7,8,9}. 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 expected^10,11, 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 nodes^12,13, 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 pathway^15,16 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.