Progressive CD4⁺ central–memory T cell decline results in CD4⁺ effector–memory insufficiency and overt disease in chronic SIV infection

Effect of infection on CD4⁺ T_EM cell differentiation from proliferating T_CM cell precursors. (A) Schema of memory T cell differentiation in RMs (18). (B) The top profiles show CD4⁺ T cells from one RM with attenuated SIVmac239(Δnef) infection (PID 387; pvl = 5,200 copies/ml) and one with progressive SIVmac239 infection (PID 579; pvl = 3,800,000 copies/ml), indicating the gating of proliferating (Ki-67⁺) CD4⁺ memory T cells. The bottom profiles show the representation of T_CM cells (CD28⁺; CCR5⁻) versus total T_EM cells (including CD28⁺, CCR5⁺ transitional T_EM cells, and CD28⁻/CCR5^dim+ mature T_EM cells) within the proliferating CD4⁺ memory compartment. (C) The figure shows cross-sectional analysis of the fractional representation of total T_EM cells (as in A) in 10 SIV⁻ RMs, 7 RMs with early plateau-phase SIVmac239 infection (PID 105; median pvl = 5,300,000 copies/ml), 8 RMs with late plateau-phase SIVmac239 infection (PID 533–878; median pvl = 660,000 copies/ml), and 12 RMs with controlled SIV infection: 9 infected with SIVmac239(Δnef) (PID 154–390; pvls < 400 copies/ml) and 3 spontaneous controllers of SIVmac239 (PID 105–147: pvls < 4,000 copies/ml). Differences were assessed by unpaired t test. (D) The profiles show the fractional representation of T_EM cells among proliferating (Ki-67⁺) CD4⁺ memory T cells from PLNs from an RM 5 d before SIVmac239 infection, at PID 150 (immediately before ART; pvl = 4,400,000 copies/ml), and at 4 (pvl = 180,000) and 8 d (pvl = 87,000) after ART initiation. (E) The profiles show the fractional representation of T_EM cells among proliferating (Ki-67⁺) CD4⁺ memory T cells from the blood of an SIVmac239-infected RM at PID 105 (immediately before ART; pvl = 3,000,000 copies/ml) and days 4 (pvl = 220,000 copies/ml), 10 (pvl = 170,000 copies/ml), and 17 (pvl = 24,000 copies/ml) after ART. The arrow indicates the development of a fully mature CD4⁺ T_EM cell population.