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

Abstract

Please note that the x axis labeling in Fig. 6 (D and E) was inadvertently cropped. The html and pdf versions are correct. The corrected fi gure is shown below. The top profi les show CD4 ϩ T cells from one RM with attenuated SIVmac239( ⌬ nef) infection (PID 387; pvl ϭ 5,200 copies/ml) and one with progressive SIVmac239 infection (PID 579; pvl ϭ 3,800,000 copies/ml), indicating the gating of proliferating (Ki-67 ϩ ) CD4 ϩ memory T cells. The bottom profi les show the representation of T CM cells (CD28 ϩ ; CCR5 Ϫ ) versus total T EM cells (including CD28 ϩ , CCR5 ϩ transitional T EM cells, and CD28 Ϫ /CCR5 dimϩ mature T EM cells) within the proliferating CD4 ϩ memory compartment. (C) The fi gure shows cross-sectional analysis of the fractional representation of total T EM cells (as in A) in 10 SIV Ϫ RMs, 7 RMs with early plateauphase SIVmac239 infection (PID 105; median pvl ϭ 5,300,000 copies/ml), 8 RMs with late plateau-phase SIVmac239 infection (PID 533 -878; median pvl ϭ 660,000 copies/ml), and 12 RMs with controlled SIV infection: 9 infected with SIVmac239( ⌬ nef) (PID 154 -390; pvls Ͻ 400 copies/ml) and 3 spontaneous controllers of SIVmac239 (PID 105 -147: pvls Ͻ 4,000 copies/ml). Differences were assessed by unpaired t test. (D) The profi les show the fractional representation of T EM cells among proliferating (Ki-67 ϩ ) CD4 ϩ memory T cells from PLNs from an RM 5 d before SIVmac239 infection, at PID 150 (immediately before ART; pvl ϭ 4,400,000 copies/ml), and at 4 (pvl ϭ 180,000) and 8 d (pvl ϭ 87,000) after ART initiation. (E) The profi les show the fractional representation of T EM cells among proliferating (Ki-67 ϩ ) CD4 ϩ memory T cells from the blood of an SIVmac239-infected RM at PID 105 (immediately before ART; pvl ϭ 3,000,000 copies/ml) and days 4 (pvl ϭ 220,000 copies/ml), 10 (pvl ϭ 170,000 copies/ml), and 17 (pvl ϭ 24,000 copies/ml) after ART. The arrow indicates the development of a fully mature CD4 ϩ T EM cell population.

S-phase entry leads to cell death in circulating T cells from HIV-infected persons

“…These studies identify a critical role for central memory T cells in maintaining memory T cell homeostastasis [5]. Central memory T cells are thought to be long-lived cells that self-renew during homeostatic proliferation, and some of these cells can differentiate into effector cells, representing a mechanism for reconstituting the effector memory pool that exists at tissue sites [5]. During HIV/SIV infection, the pool of mucosal effector CD4ϩ T cells is massively depleted early in infection [6,7], whereas central memory T cells are relatively preserved.…”

“…One compelling explanation for differences in CD4 and CD8 T cell homeostasis in HIV infection is derived from recent studies in SIV-infected macaques. These studies identify a critical role for central memory T cells in maintaining memory T cell homeostastasis [5]. Central memory T cells are thought to be long-lived cells that self-renew during homeostatic proliferation, and some of these cells can differentiate into effector cells, representing a mechanism for reconstituting the effector memory pool that exists at tissue sites [5].…”

Regulatory T cells and chronic immune activation in human immunodeficiency virus 1 (HIV-1)-infected children

“…Defective immune responses against HIV-1 and other viral/microbial agents result in a chronic immune activation that plays a central role in disease progression [1]. T lymphocyte activation induced by antigenic stimulation may lead to a transient and partial restoration of memory CD4 + lymphocytes [2]. However, chronic immune activation is overwhelmingly detrimental; it results in the generation of activated T cells that are targets for the virus, thus further driving viral replication and CD4 cell depletion [3,4].…”

Preferential Cytolysis of Peripheral Memory CD4 + T Cells by In Vitro X4-Tropic Human Immunodeficiency Virus Type 1 Infection before the Completion of Reverse Transcription

“…The nonproductive infection of memory CD4 ϩ T cells has little effect on virus proliferation. Instead, the direct killing of memory CD4 ϩ T cells damages the host's immune response to the virus, as the central role of memory CD4 ϩ T cells has been demonstrated in rhesus macaques infected with SIV (52,66). Furthermore, necrotic cells release intracellular molecules through disrupted plasma membranes and elicit proinflammatory responses.…”