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 (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

Inositol-1,4,5-trisphosphate receptor-mediated Ca2+ waves in pyramidal neuron dendrites propagate through hot spots and cold spots

We studied inositol-1,4,5-trisphosphate (IP3) receptor-dependent intracellular Ca2+ waves in CA1 hippocampal and layer V medial prefrontal cortical pyramidal neurons using whole-cell patch-clamp recordings and Ca2+ fluorescence imaging. We observed that Ca2+ waves propagate in a saltatory manner through dendritic regions where increases in the intracellular concentration of Ca2+ ([Ca2+]i) were large and fast (‘hot spots’) separated by regions where increases in [Ca2+]i were comparatively small and slow (‘cold spots’). We also observed that Ca2+ waves typically initiate in hot spots and terminate in cold spots, and that most hot spots, but few cold spots, are located at dendritic branch points. Using immunohistochemistry, we found that IP3 receptors (IP3Rs) are distributed in clusters along pyramidal neuron dendrites and that the distribution of inter-cluster distances is nearly identical to the distribution of inter-hot spot distances. These findings support the hypothesis that the dendritic locations of Ca2+ wave hot spots in general, and branch points in particular, are specially equipped for regenerative IP3R-dependent internal Ca2+ release. Functionally, the observation that IP3R-dependent [Ca2+]i rises are greater at branch points raises the possibility that this novel Ca2+ signal may be important for the regulation of Ca2+-dependent processes in these locations. Futhermore, the observation that Ca2+ waves tend to fail between hot spots raises the possibility that influences on Ca2+ wave propagation may determine the degree of functional association between distinct Ca2+-sensitive dendritic domains