Reduction in T cell apoptosis in patients with HIV disease following antiretroviral therapy.

Patients with HIV infection manifest increased T lymphocyte apoptosis. This study investigated the influence of antiretroviral therapy (ART) upon lymphocyte apoptosis in 23 HIV-infected adults naive to protease inhibitors. Patients were enrolled in a treatment trial consisting of Nelfinavir (NFV), d4T, or NFV + d4T for 24 weeks, followed by triple therapy (NFV + reverse transcriptase inhibitors) for an additional 24 weeks. Spontaneous T cell apoptosis in cultured PBMC decreased by 23.67 +/- 18.2% (P < 0.006) at 48 weeks and plasma HIV RNA decreased by 1.79 +/- 0.59 log(10) RNA copies/ml (P < 0.001). The absolute decrease and slope of T cell apoptosis correlated with plasma virus load and with activated CD8 T cells and was inversely correlated with CD4 T cells. We conclude that reduction in chronic antigenic stimulation and the absence of cellular signals elicited by viral products contribute to the rescue of T lymphocytes from apoptosis, which facilitates immunologic recovery in ART-treated patients.

Inhibition of sphingolipid synthesis down-modulates CD4 expression by peripheral blood T lymphocytes and T lymphoma cells.

Recent studies have demonstrated that L-cycloserine, an inhibitor of sphingolipid biosynthesis, interferes with the life cycle of HIV. Experiments with human T cells and CD4+ T lymphoma cells were performed to examine possible mechanisms. L-CS selectively down-modulated CD4 expression without affecting the expression of CD3 and CD8. L-cycloserine also inhibited T cell mitogen responses without affecting IL-2 production. Membranes prepared from L-CS-treated T lymphoma cells showed changes in lipid composition that correlated with changes in membrane microviscosity. These results suggest that normal expression of CD4 may depend upon sphingolipid biosynthesis in contrast with the other CD determinants measured. Selective inhibition of CD4 by L-cycloserine together with its antiviral effects may offer a novel approach for interfering with HIV cell binding and infectivity.

IgD-receptor-positive human T lymphocytes. I. Modulation of receptor expression by oligomeric IgD and lymphokines.

Studies with human myeloma-derived IgD have demonstrated the existence of IgD-R on peripheral blood T cells. These receptors, which are detected by rosetting with IgD-coated ox E (IgD-rosette-forming cells), are competitively inhibited by IgD, but not by IgM or IgG. Similar results were obtained with human T cell clones and T hybridomas derived from such clones either by rosetting assays or by staining with biotinylated-IgD. In agreement with studies of murine IgD-R+ cells, human IgD-R can be up-regulated by exposure of peripheral blood T cells, T cell clones, and hybridomas derived from such clones, to oligomeric IgD, but not monomeric IgD. Human IgD-R can also be induced by IL-2, IL-4, and IFN-gamma. In contrast with studies of murine IgD-R, which are expressed primarily by CD4+ cells, phenotyping studies show that both the CD4+ and CD8+ human T cell subsets are capable of expressing IgD-R.