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 immunodeficiency, 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. JEM