Primary simian immunodeficiency virus (SIV) infections of rhesus macaques result in the dramatic depletion of CD4+ CCR5+ effector–memory T (TEM) cells from extra-lymphoid effector sites, but in most infections, an increased rate of CD4+ memory T cell proliferation appears to prevent collapse of effector site CD4+ TEM cell populations and acute-phase AIDS. Eventually, persistent SIV replication results in chronic-phase AIDS, but the responsible mechanisms remain controversial. Here, we demonstrate that in the chronic phase of progressive SIV infection, effector site CD4+ TEM cell populations manifest a slow, continuous decline, and that the degree of this depletion remains a highly significant correlate of late-onset AIDS. We further show that due to persistent immune activation, effector site CD4+ TEM cells are predominantly short-lived, and that their homeostasis is strikingly dependent on the production of new CD4+ TEM cells from central–memory T (TCM) cell precursors. The instability of effector site CD4+ TEM cell populations over time was not explained by increasing destruction of these cells, but rather was attributable to progressive reduction in their production, secondary to decreasing numbers of CCR5− CD4+ TCM cells. These data suggest that although CD4+ TEM cell depletion is a proximate mechanism of immunodeficiency, the tempo of this depletion and the timing of disease onset are largely determined by destruction, failing production, and gradual decline of CD4+ TCM cells.

Depletion of CD8+ lymphocytes during acute simian immunodeficiency virus (SIV) infection of rhesus macaques (RMs) results in irreversible prolongation of peak-level viral replication and rapid disease progression, consistent with a major role for CD8+ lymphocytes in determining postacute-phase viral replication set points. However, we report that CD8+ lymphocyte depletion is also associated with a dramatic induction of proliferation among CD4+ effector memory T (TEM) cells and, to a lesser extent, transitional memory T (TTrM) cells, raising the question of whether an increased availability of optimal (activated/proliferating), CD4+/CCR5+ SIV “target” cells contributes to this accelerated pathogenesis. In keeping with this, depletion of CD8+ lymphocytes in SIV− RMs led to a sustained increase in the number of potential CD4+ SIV targets, whereas such depletion in acute SIV infection led to increased target cell consumption. However, we found that the excess CD4+ TEM cell proliferation of CD8+ lymphocyte–depleted, acutely SIV-infected RMs was completely inhibited by interleukin (IL)-15 neutralization, and that this inhibition did not abrogate the rapidly progressive infection in these RMs. Moreover, although administration of IL-15 during acute infection induced robust CD4+ TEM and TTrM cell proliferation, it did not recapitulate the viral dynamics of CD8+ lymphocyte depletion. These data suggest that CD8+ lymphocyte function has a larger impact on the outcome of acute SIV infection than the number and/or activation status of target cells available for infection and viral production.

Material Supplementary 6.DC1http://www.jimmunol.org/content/suppl/2010/07/06/jimmunol.090262

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.

Memory CD4+ T cell homeostasis and AIDS progression are independent of naive CD4+ T cells in SIV infection of nonhuman primates.