PROGRESSIVE LOSS OF CD8(-MEDIATED CONTROL OF A GAMMA-HERPESVIRUS IN THE ABSENCE OF CD4(+) T-CELLS() T CELL)

A unique experimental model has been developed for dissecting the inte grity of CD8(+) T cell-mediated immunity to a persistent gammaherpesvi rus under conditions of CD4(+) T cell deficiency. Respiratory challeng e of major histocompatibility complex class II -/- and +/+ C57BL/6J mi ce with the murine gammaherpesvirus 68 (MHV-68) leads to productive in fection of both lung and adrenal epithelial cells. Virus titers peak w ithin 5-10 d, and are no longer detected after day 15. Persistent, lat ent infection is established concurrently in splenic and lymph node B cells, with higher numbers of MHV-68(+) lymphocytes being found in all lymphoid sites analyzed from the +/+ mice concurrent with the massive , but transient splenomegaly that occurred only in this group. From da y 17, however, the numbers of infected B lymphocytes were consistently higher in the -/- group, while the frequency of this population dimin ished progressively in the +/+ controls. Infectious MHV-68 was again d etected in the respiratory tract and the adrenals of the -/- (but not the +/+) mice from day 22 after infection. The titers in these sites r ose progressively, with the majority of the -/- mice dying between day s 120 and 133. Even so, some CD8(+) effectors were still functioning a s late as 100 d after infection. Depletion of CD8(+) T cells at this s tage led to higher virus titers in the -/- lung, and to the developmen t of wasting in some of the -/- mice. Elimination of the CD8(+) T cell s from the +/+ group (day 80) increased the numbers of MHV-68(+) cells in the spleen, but did not reactivate the infection in the respirator y tract. The results are consistent with the interpretation that CD8() T cell-mediated control of this persistent gammaherpesvirus is progr essively lost in the absence of the CD4(+) T cell subset. This paralle ls what may be happening in AIDS patients who develop Kaposi's sarcoma and various Epstein Barr virus-associated disease processes.