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

Primary simian immunodeficiency virus ( SIV) infections of rhesus macaques result in the dramatic depletion of CD4(+) CCR5(+) effector-memory T ( T-EM) 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(+) T-EM 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(+) T-EM 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(+) T-EM cells are predominantly short-lived, and that their homeostasis is strikingly dependent on the production of new CD4(+) T-EM cells from central -memory T ( T-CM) cell precursors. The instability of effector site CD4(+) T-EM 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(+) T-CM cells. These data suggest that although CD4(+) T-EM cell depletion is a proximate mechanism of immuno-deficiency, the tempo of this depletion and the timing of disease onset are largely determined by destruction, failing production, and gradual decline of CD4(+) T-CM cells.