EFFECTS OF T(H)1 AND T(H)2 CYTOKINES ON CD8(+) CELL RESPONSE AGAINST HUMAN-IMMUNODEFICIENCY-VIRUS - IMPLICATIONS FOR LONG-TERM SURVIVAL

CD8(+) cells from long-term survivors [LTS; infected with human immunodeficiency virus (HIV) for 10 or more years and having CD4(+) cell counts of greater than or equal to 500 cells per mu l] have a 3-fold greater ability to suppress HIV replication than do CD8(+) cells from patients who have progressed to disease (progressors) during the same time period. A change in the pattern of cytokines produced in the host from those that typically favor cell-mediated immunity (T helper 1, T(H)1 or type 1) to those that down-regulate it (T helper 2, T(H)2 or type 2) was investigated as a cause of this reduced CD8(+) cell anti-HIV function. Treatment of CD8(+) cells from LTS with the T(H)1 cytokine interleukin (IL)-2 enhanced their anti-HIV activity, whereas exposure of these cells to T(H)2 cytokines IL-4 or IL-10 reduced their ability to suppress HIV replication and to produce IL-2. IL-2 could prevent and reverse the inhibitory effects of IL-4 and IL-10. Moreover, prolonged exposure of CD8(+) cells from some progressors to IL-2 improved the ability of these cells to suppress HIV replication. These observations support previous findings suggesting that strong CD8(+) cell responses play an important role in maintaining an asymptomatic state in HIV infection. The data suggest that the loss of CD8(+) cell suppression of HIV replication associated with disease progression results from a shift in cytokine production within the infected host from a T(H)1 to a T(H)2 pattern. Modulation of these cytokines could provide benefit to HIV-infected individuals by improving their CD8(+) cell anti-HIV activity.