Profound CD4⁺/CCR5⁺ T cell expansion is induced by CD8⁺ lymphocyte depletion but does not account for accelerated SIV pathogenesis

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 (T _EM) cells and, to a lesser extent, transitional memory T (T _TrM) 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⁺ T_EM and T_TrM 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.