Enhanced interferon-gamma by CD8(+) CD28(-) lymphocytes from HIV+ patients

Flow cytometric analysis of T cells from HIV+ and normal individuals activa ted for 15 hr showed that the percentage of cells producing interferon-gamm a (INF gamma) was enhanced approximately threefold (39 compared to 14%) in the HIV+ CD8(+) population. Activation modes, other than anti-CD3 with PMA, were ineffective, and in no case did the percentage of HIV+ CD4(+) T cells show increased INF gamma production over controls. Enhanced INF gamma prod uction was not induced by either anti-CDS or PMA alone, or anti-CD3 or ConA with anti-CD28, or enhanced by N-acetylcysteine. In contrast to INF gamma production, the percentage of CD4(+) T cells producing interleukin-2 (IL-2) greatly exceeded that of the CD8(+) T cells. The results from flow cytomet ry analyses of HIV+ CD8(+) T cells was supported by quantitative analysis o f INF gamma mRNA (by PCR) and INF gamma secretion by ELISA. These methods s howed a sixfold and three- to fivefold increase, respectively, on a per cel l basis. As HIV infection progresses, as shown by loss of CD4(+) T cells, t he proportion of CD8(+) CD28(-) T cells increases, and it is this T cell su bset that is responsible for 80% or more of the enhanced INF gamma producti on. The enhanced INF gamma in HIV+ patients derives from two factors: the i ncrease in CD8(+) CD28(-) cells to 70% and the percentage producing INF gam ma (60%, compared to 21% for CD8(+) CD28(+) cells). Our findings of a subst antial increase in INF gamma production in HIV infection arising from the i ncreased number of CD8(+) CD28(-) T cells are compatible with clinical stud ies which show elevated INF gamma in HIV+ serum and INF gamma producing CD8 (+) T cells dominating HIV+ lymph nodes. We also found a significantly decr eased proliferative response of the HIV+-derived CD8(+) T cell fraction wit h coactivator anti-CD-28, in contrast to PMA (with anti-CD3), which is prob ably a reflection of the diminished population of CD8(+) CD28(+) T cells in HIV+ donors compared to normal donors (30.7 compared to 67.9%).