Large granular lymphocytes are universally increased in human, macaque, and feline lentiviral infection.

Large granular lymphocytes (LGLs) have only been anecdotally reported in HIV infection. We previously reported an LGL lymphocytosis in FIV-infected cats associated with a rise in FIV proviral loads and a marked neutropenia that persisted during chronic infection. Extensive immunophenotyping of peripheral blood mononuclear cells in cats chronically infected with FIV were identified LGLs as CD8lo(+)FAS(+); this cell population expanded commensurate with viral load. CD8lo(+)FAS(+) cells expressed similar levels of interferon-γ compared to CD8lo(+)FAS(+) cells from FIV-naive control animals, yet CD3ɛ expression, which was increased on total CD8(+) T cells in FIV-infected cats, was decreased on CD8lo(+)FAS(+) cells. Down-modulation of CD3 expression was reversed after culturing PBMC for 3 days in culture with ConA/IL-2. We identified CD8lo(+)FAS(+) LGLs to be polyclonal T cells lacking CD56 expression. Blood smears from HIV-infected individuals and SIVmac239-infected rhesus macaques revealed increased LGLs compared to HIV/SIV negative counterparts. In humans, there was no correlation with viral load or treatment and in macaques the LGLs arose in acute SIV infection with increases in viremia. This is the first report describing and partially characterizing LGL lymphocytosis in association with lentiviral infections in three different species.

Effect of a four-week course of interleukin-10 on cytokine production in a placebo-controlled study of HIV-1-infected subjects.

Interleukin (IL)-10 suppresses synthesis of the pro-inflammatory cytokines tumor necrosis factor (TNF)alpha, IL-1beta, and interferon (IFN)gamma. Since pro-inflammatory cytokines have been implicated in the production of human immunodeficiency virus type 1 (HIV-1), cytokine synthesis in whole blood cultures were determined during a 4-week course of subcutaneous IL-10 injections in 33 HIV-1-infected patients. Patients were randomized into four groups: placebo (nine), IL-10 at 1 microg/kg/day (nine), IL-10 at 4 microg/kg/day (six) and IL-10 at 8 microg/kg three times per week (nine). Whole blood was obtained at the beginning and conclusion of the study and was stimulated for 24 hours with the combination of IL-18 plus lipopolysaccharide. TNFalpha production in stimulated whole blood was reduced three and six hours after the first injection of IL-10 compared to subjects injected with the placebo. After four weeks of treatment, production of IFNgamma was suppressed in a greater number of patients in the IL-10 treatment groups compared to subjects in the placebo group. Similarly, IL-1beta production was lower in the IL-10 treatment groups compared to subjects receiving placebo. In contrast, after four weeks of IL-10, circulating levels of the anti-inflammatory TNF soluble receptor p55 increased dose-dependently compared to placebo subjects. Patient heterogeneity and small sample size presented difficulties in establishing statistical significance. Although the cytokine changes in our study did not demonstrate statistically significant changes, the data nevertheless reveal that four weeks of IL-10 therapy in HIV-1 infected subjects produced the anticipated suppression of pro-inflammatory cytokines.