Insufficient production and tissue delivery of CD4+ memory T cells in rapidly progressive simian immunodeficiency virus infection.

The mechanisms linking human immunodeficiency virus replication to the progressive immunodeficiency of acquired immune deficiency syndrome are controversial, particularly the relative contribution of CD4+ T cell destruction. Here, we used the simian immunodeficiency virus (SIV) model to investigate the relationship between systemic CD4+ T cell dynamics and rapid disease progression. Of 18 rhesus macaques (RMs) infected with CCR5-tropic SIVmac239 (n=14) or CXCR4-tropic SIVmac155T3 (n=4), 4 of the former group manifested end-stage SIV disease by 200 d after infection. In SIVmac155T3 infections, naive CD4+ T cells were dramatically depleted, but this population was spared by SIVmac239, even in rapid progressors. In contrast, all SIVmac239-infected RMs demonstrated substantial systemic depletion of CD4+ memory T cells by day 28 after infection. Surprisingly, the extent of CD4+ memory T cell depletion was not, by itself, a strong predictor of rapid progression. However, in all RMs destined for stable infection, this depletion was countered by a striking increase in production of short-lived CD4+ memory T cells, many of which rapidly migrated to tissue. In all rapid progressors (P <0.0001), production of these cells initiated but failed by day 42 of infection, and tissue delivery of new CD4+ memory T cells ceased. Thus, although profound depletion of tissue CD4+ memory T cells appeared to be a prerequisite for early pathogenesis, it was the inability to respond to this depletion with sustained production of tissue-homing CD4+ memory T cells that best distinguished rapid progressors, suggesting that mechanisms of the CD4+ memory T cell generation play a crucial role in maintaining immune homeostasis in stable SIV infection.

Innate IL-10 promotes the induction of Th2 responses with plasmid DNA expressing HIV gp120.

Like most DNA vaccines, intramuscular immunization with plasmid DNA coding for influenza virus haemagglutinin (HApDNA) induced Th1 responses and IgG2a antibodies in mice. However, plasmid DNA coding for HIV gp120 (gp120pDNA) induced Th2-biased responses and predominantly IgG1 antibodies. Responses to gp120pDNA switched to a Th1-type in IL-10-defective mice and to exclusively IgG2a antibodies in IL-4-defective mice. Conversely, antigen-specific IFN-gamma production induced by gp120pDNA or HApDNA was reduced in IL-12-defective mice, whereas addition of plasmid DNA coding for IL-12 enhanced Th1 responses. Plasmid DNA stimulated IL-10 and IL-12 production by macrophages and dendritic cells (DCs) in vitro and anti-IL-10 antibodies enhanced IL-12 production and DC maturation in response to gp120pDNA. Our findings suggest that T cell responses induced by DNA vaccines is influenced by the nature of the antigen, and that the induction of Th2-biased responses with gp120pDNA is mediated in part through the stimulation of innate IL-10, which inhibits activation of DCs that direct the induction of Th1 cells.